TAP Vol 1 Issue 4 by Harborside Press LLC

Important perspectives 2, 3, 6, 10, 11

Oncology drug news 27

VOLUME 1, ISSUE 4

Financial survival in oncology 30

SEPTEMBER 2010 ASCOPost.com

Editor-in-Chief, James O. Armitage, MD

Breast Cancer

Radiation Therapy Not Necessary for Some Elderly Patients with ER-positive Breast Cancer

Bevacizumab, ODAC, and the FDA

By Caroline Helwick

lderly women with estrogen receptor (ER)-positive early breast cancer may be able to safely forgo radiation therapy after lumpectomy, according to data from a large Intergroup trial presented at the 2010 ASCO Annual Meeting. The only significant benefit for the addition of radiation therapy to tamoxifen was a small reduction in local recurrence—an absolute 7% decline compared to tamoxifen alone.

TamRT n = 317

0.8

n (10 yr)

Proportion

0.6

0.4

Breast tumor recurrence

6 (2%)

Ultimate mastectomy

4 (2%)

Second primary cancer

36 (12%)

Distant metastasis

21 (5%)

Death 0.2

0.0

“At 10 years’ follow-up, 95% of the patients in each group had no distant metastases, which is essentially a 95% cure rate,” said Kevin S. Hughes, MD, a member of the Department of Surgical Oncology at Massachusetts General Hospital, Boston. The findings add further evidence that women aged 70 and older with early-stage breast cancer can undergo lumpectomy plus tamoxifen therapy alone without compromising their survival. Dr. Hughes made it clear, however, that the results cannot be applied to younger wom21 women en, for whom radiation therapy is the Tam n = 319 standard of care. n (10 yr) Dr. Hughes presented the results P = .0001 27 (9%) on behalf of the Cancer and Leukemia Group B (CALGB), the RaNS 10 (4%) diation Therapy Oncology Group NS 33 (9%) (RTOG), and the Eastern CooperaNS 16 (5%) tive Oncology Group (ECOG).

157 (33%)

156 (33%)

Death from other causes

145

148

Death from breast cancer

Years

Recurrence Rate Differed

Fig. 1: Outcomes of radiotherapy/tamoxifen or tamoxifen alone after lumpectomy in elderly patients with estrogen receptor-positive breast cancer. Differences are small. Shaded green area represents 21 women (7%) who benefited by the addition of radiation compared to tamoxifen alone. Patient numbers (n) are actual numbers at 12 years’ follow-up, whereas percentages in parentheses represent the actuarial rate at 10 years. NS = not significant; Tam = tamoxifen; TamRT = tamoxifen/radiotherapy. Courtesy of Kevin S. Hughes, MD.

CALGB 9343 included 636 women age 70 and older with stage I (tumor size ≤ 2 cm), ER-positive (or ER-indeterminate), node-negative breast cancer who had a lumpectomy with negative margins. They were randomly assigned to receive tamoxifen (n = 319) or tamoxifen plus radiacontinued on page 2

Leukemia

Gabriel Hortobagyi, MD

he Oncologic Drugs Advisory Committee (ODAC)a of the FDA has recommended that the Agency revoke approval of bevacizumab (Avastin) in first-line treatment of metastatic breast cancer. The FDA will decide whether or not to accept this recomendation later in the year. E2100, AVADO, and RIBBON-1 clearly showed that the addition of bevacizumab increases response rate and time to progression, although for reasons not yet clear, overall survival (OS) was not prolonged, nor was there an apparent nonsignificant trend for improved survival. This makes the situation with bevacizumab continued on page 7

Dr. Hortobagyi attended the ODAC meeting as a consultant to Genentech and made a presentation in support of preserving and expanding the indications for bevacizumab. Dr. Hortobagyi indicated that “For this meeting [ODAC, July 20, 2010], the company [Genentech] provided my travel and lodging expenses. I have otherwise no financial interest in the outcome of this meeting.” a See page 2 for perspective from ODAC members.

See page 43

The full transcript of the July 20, 2010, ODAC meeting on bevacizumab may be obtained online at http://tiny. cc/2r9x6.

Or use your smartphone to access the transcript via the 2D barcode, above.

Bosutinib May Have a Major Role in CML By Alice Goodman

MORE IN THIS ISSUE

n the heels of the positive studies of nilotinib (Tasigna) and dasatinib (Sprycel) as first-line therapy for chronic-phase chronic myeloid leukemia (CML), promising results for another tyrosine kinase inhibitor—bosutinib—were presented at the 2010 ASCO Annual Meeting. Two separate studies reported at the meeting showed that bosutinib was effective as Use your smartphone to view the original abstracts as presented at ASCO’s 2010 Annual Meeting. See page 43 for more information about using 2D barcodes

second- and third-line therapy in patients for whom imatinib and other therapies have failed. The first study found that half of the patients who were either imatinib-resistant or imatinib-intolerant achieved a complete cytogenetic response (CCyR) with bosutinib.1 The second study suggested that bosutinib was also effective as third-line therapy in chronic-phase CML, after failure on first-line imatinib and second-line dasatinib.2 “We see very good activity for bosutinib in both second- and third-line therapy, with high levels of response,” said lead author of the first study and senior author of the second study, Jorge E. Cortes, MD,

2010 ASCO Annual Meeting Coverage

Breast cancer �� 1 Hematology �� 1 Head and neck cancer �� 16 Lung cancer �� 25 Melanoma: A New Paradigm �� 3 Direct from ASCO �� 18

continued on page 8

A Harborside Press Publication

The ASCO Post | SEPTEMBER 2010

PAGE 2

Perspective

ODAC Voting Members Discuss Panel’s Recommendation about Bevacizumab in Advanced Breast Cancer

he recent recommendation by the Oncologic Drugs Advisory Committee (ODAC) to withdraw conditional approval of bevacizumab (Avastin) in combination with chemotherapy for previously untreated metastatic breast cancer has been received with controversy. While many are genuinely concerned about withdrawal of an effective drug, others—such as the author of a recent editorial in The Wall Street Journal (August 18, 2010)—have distorted the science and facts to arWyndham Wilson, MD, PhD gue that the decision was political and that ODAC is beholden to the politics of the FDA and Congress. Unfortunately, these latter arguments serve no purpose but to promote an agenda at the expense of breast cancer patients. It is important that the breast cancer community rest assured that ODAC is an independent, unbiased panel of experts in oncology whose mission is to provide their best objective scientific and clinical recommendations to the FDA for drug approval. In my experience on this panel, I have never witnessed improper influence from any government agency. In fact, the FDA has taken great steps to maintain the independence and objectivity of ODAC. The FDA’s mandate is to protect the American public by approving drugs that are effective while posing acceptable risks. One need only remember events surrounding the use of thalidomide in the 1950s—the drug caused immeasurable suffering in babies born without limbs, and the FDA blocked approval in the United States. Many more examples exist of the role the FDA serves in protecting the American public from unsafe drugs and/or indications and unscrupulous promotion. Indeed, given that fewer than 1% of drugs ever show significant benefit, it is essential that the American people feel confident that an approved drug will be of help to them and not promoted for economic purposes. I present this as backdrop to the controversy over bevacizumab, which is a good example of a drug that has benefit but also significant side effects. When evaluating a drug, one needs to weigh these factors within the context of the disease. For example, in lung and colon cancers, the therapeutic effect of bevacizumab on survival was relatively short and the toxicity significant, but the benefit was nonetheless meaningful because few drugs prolong survival in these devastating diseases. In breast cancer, however, patients experienced only a 1- to 2-month delay in disease progression—without improved survival—and had serious toxicity. The panel recognized that a drug may improve a patient’s quality of life without prolonging survival, and that is a very legitimate reason to approve a drug. Unfortunately, the manufacturer (Genentech) did not officially incorporate quality-of-life measurements in their investigations, and the quality-of-life data they did present suggested there was no improvement. In fact, Genentech’s response was, “We are not making patients worse.” This is not sufficient. We need to make patients better. It is understandable that some oncologists may want bevacizumab to remain available with a breast cancer indication because it could benefit a subset of yet-tobe-identified patients. Of course, this requires controlled studies employing biomarkers and cannot be presaged through the art of medicine. Indeed, bevacizumab

Radiation in Older Women continued from page 1

tion (n = 317), and then followed for a median time of 12 years. The current analysis was of outcomes at 10 years. No significant differences were observed between the groups with respect to breast preservation rates, breast cancer–specific survival, See page 43 or overall survival

(Fig. 1), Dr. Hughes reported. In-breast recurrence, however, was inferior when radiation therapy was eliminated. Local recurrences were observed in 6/317 (2%) in the tamoxifen-radiotherapy arm and 27/319 (9%) in the tamoxifen-only arm (P = .0001). Dr. Hughes remarked that this was a small benefit. “We would have to irradiate 319 women to prevent 21(7%) in-breast recurrences,” he noted. Overall survival tended to be low be-

does not target a specific driving oncogenic pathway. Angiogenesis is a complex phenotype, and all tumors show some degree of this process. We must not lose sight of the big picture, which is that most patients with metastatic breast cancer do not achieve meaningful benefit, and in the absence of benefit, only the potential of harm remains. Indeed, it is important to recognize that although many breast cancer survivors are currently benefiting from a combination of bevacizumab and chemotherapy, the results of the randomized studies indicate that it is the chemotherapy drug and not bevacizumab that is providing the significant benefit. —Wyndham Wilson, MD, PhD, ODAC Chair, Chief Lymphoid Therapeutics Section, Center for Cancer Research, National Cancer Institute

■

n December 2007, I voted to approve bevacizumab for advanced breast cancer on the basis of the E2100 study. At the time, it was noted that the 22% response rate to paclitaxel was surprisingly low and the apparent difference with the combination might be exaggerated. The higher response rate with bevacizumab suggests drug activity. However, a 1% increased incidence of death with the combination observed in all the clinical trials weighed heavily not only on me, but on breast cancer advocates Joanne Mortimer, MD at the hearing. E2100 was not meant to be a registration trial. Only grade 3–5 toxicities were reported, and there is no record of patients discontinuing therapy because of toxicity. The FDA review of the data found that 10% of patients lacked CT scans and approximately one-third of patients were not followed until progression or end of study. E2100 is considered the most positive bevacizumab trial, and the missing data are of concern. The additional data from AVADO and RIBBON-1 supported an increased response rate, but also confirmed the increased toxicity and lack of survival advantage with bevacizumab. Like the majority of panel members, I could not recommend approval. —Joanne Mortimer, MD, Director of the Women’s Cancers’ Program and Professor of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California

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See page 5 for perspective from members of the oncology community on the role of bevacizumab in breast cancer. Share your thoughts. Write to Editor@ASCOPost.com. Disclosure of Potential Conflicts of Interest Wyndham Wilson, MD, PhD: Dr. Wilson has no financial interest or other relationship with the manufacturers of any products discussed in this report. Joanne Mortimer, MD: Dr. Mortimer has no financial interest or other relationship with the manufacturers of any products discussed in this report.

cause these were older women who died of other causes. ASCO President George Sledge, MD, of Indiana University School of Medicine, commented at a press briefing, “We have many elderly patients who have a hard time getting back and forth to radiotherapy appointments for 6 to 7 weeks. This study gives those patients real comfort that they are not missing out on a lifesaving treatment,” he said. “But there are going to be patients who look at the data and think that a 6% to 7% reduction

See page 43

in in-breast recurrence is important to them because they want to avoid the need for retreatment. This study says that there are options for physicians and patients, and that is its value.”

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Reference 1. Hughes KS, Schnaper LA, Cirrincione C, et al: Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer. 2010 ASCO Annual Meeting. Abstract 507. Presented June 7, 2010.

ASCOPost.com | SEPTEMBER 2010

PAGE 3

Perspective Melanoma

Immunotherapy for Melanoma: Time for a New Paradigm?

Editorial Board James O. Armitage, MD Editor-in-Chief

James L. Mulshine, MD Rush University Medical Center

Elizabeth Reed, MD Deputy Editor Division of Hematology & Oncology University of Nebraska Medical Center Omaha, Nebraska

Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic

ASSOCIATE EDITORS

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Joseph S. Bailes, MD Texas Oncology Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Michael P. Link, MD Stanford University Medical Center

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com

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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Alice Goodman, Caroline Helwick, Matthew Stenger

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations Artwork on page 33 by Alex and David and Baker, DNA Illustrations Financial disclosure information available at ASCOPost.com.

By Vernon K. Sondak, MD

he past 4 decades have seen substantial research on immunotherapy, particularly with vaccines, for treatment and prevention of melanoma recurrence. Reasons behind this research effort include the lack of effective conventional therapies for metastatic and high-risk melanoma, the now century-old observation that melanoma patients occasionally have dramatic responses to immunologic manipulations, and most importantly, our continually expanding understanding of the human immune system and the mechanisms of antitumor immune responses. But despite the enormous promise of vaccines to provide nontoxic protection against melanoma growth, the actual results have been disappointing, with several high-profile vaccine clinical trials failing to demonstrate a benefit—and some actually suggesting vaccination was associated with a worse outcome. Available vaccines have uniformly failed to produce significant levels of

We now have dramatic proof that ‘taking the brakes off the immune system’ can offer new hope to our patients with metastatic melanoma. objective response in patients with metastatic melanoma. A review of the National Cancer Institute experience with 440 patients (mostly melanoma patients) who received a total of 541 different vaccines demonstrated only four complete and nine partial responses, for an overall response rate of 3%. A randomized trial comparing a peptide-pulsed dendritic cell vaccine to single-agent dacarbazine chemotherapy in patients with meta-

static melanoma showed a similarly low level of responses to the vaccine and disappointing median time to progression and median survival (3.2 and 9.0 months, respectively), which were no different from those for dacarbazine alone.

Putting Results in Context These disappointing clinical results are perhaps not so surprising when one considers that most vaccines generate only weak immune responses, and it is likely that any immune responses we do detect are not directly relevant to immune-mediated tumor destruction, because detection of an immune response to date has not correlated directly with tumor regression. It is fair to say that the entire paradigm of repeated vaccination with tumor-associated antigens as a nontoxic way of stimulating the immune system to recognize and reject melanoma has failed to live up to expectations, and needs to be reevaluated if not replaced. The disappointing results of the past need to be placed in the context of exciting developments in our understanding of the human immune system. Costimulatory molecules on T cells have been identified and shown to augment the T cell’s response to antigens, while inhibitory molecules have been found to rapidly turn off the same cell’s response. It has become increasingly apparent that the balance between these stimulatory and inhibitory signals influences not only the magnitude of the antitumor immune response, but also the likelihood of toxicity, manifested in autoimmune adverse effects. This has allowed a new paradigm to emerge, namely “inhibiting the inhibitors,” or perhaps more colorfully put, “taking the brakes off the immune system.”

Toxicity–Response Link The first agents capable of inhibiting the inhibitory molecules on T cells to enter clinical trials in melanoma have been the anti-CTLA4 continued on page 4

The ASCO Post | SEPTEMBER 2010

PAGE 4

Perspective

Immunotherapy for Melanoma continued from page 3

antibodies. CTLA4 has emerged as the prototypical inhibitory molecule, expressed almost as soon as T-cell activation by antigen begins, and its absence or blockade is associated with severe autoimmune manifestations. In the earliest phases of clinical trials, treatment with even a single dose of anti-CTLA4 antibody—without any type of vaccine or other immunostimulant—resulted in the arrest of melanoma growth and even in dramatic tumor shrinkage in some cases. But it also resulted in profound autoimmune toxicity in some patients, including immune-related colitis, hepatitis, and even hypophysitis (autoimmune pituitary dysfunction). Repeatedly, it appeared that patients who experienced autoimmune toxicities were also most likely to show benefit in terms of tumor response. Clearly, the success of CTLA4 blockade represented a new paradigm, where toxicity of therapy was accepted—perhaps even desired—in order to stimulate a sufficiently robust immune response to check or even reverse melanoma growth.

Dramatic Results The value of this new paradigm over the old one has now been established, with the recent presentation (at the 2010 ASCO Annual Meeting) of the results of a randomized phase III trial comparing patients with melanoma treated with a vaccine (gp100) to those treated with ipilimumab, one of two anti-CTLA4 antibodies to enter human testing, alone or with the gp100 vaccine. In particular, it was hoped that the coadministration of the anti-CTLA4 antibody and the vaccine would “steer”

the immune system in the right direction—and away from toxicity. The results of this trial were dramatic—and in some ways unexpected. The gp100 vaccine “control” arm, as in the past trials of vaccines, had a very low response rate and short progression-free and overall survival times, but limited toxicity. The two ipilimumab arms (alone or with vaccine), had far more toxicity but better response rates and, most importantly, statistically significant improvement in overall survival compared to vaccine alone. Unexpectedly, adding the gp100 vaccine to the ipilimumab antibody did not improve the antitumor effects, nor did it lessen the autoimmune toxicity.

Conclusion Only time will tell what role, if any, vaccines will ultimately play in the treatment of melanoma patients. But there is no question that improvement in our understanding of the immune system and the development of antibodies capable of both augmenting the immune response to self-antigens and blocking the negative regulatory influences on the antitumor immune response have resulted in a new paradigm for treating melanoma patients with immunotherapy. While there is a clear need for additional clinical trials, we now have dramatic proof that taking the brakes off the immune system can offer new hope to our patients with metastatic melanoma, and perhaps someday soon to patients with other stages and types of cancer.

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Suggested Reading Gogas H, Ioannovich J, Dafni U, et al: Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709-718, 2006. Hodi FS, O’Day SJ, McDermott DF, et

al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med June 14, 2010 (epub ahead of print). Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372-8377, 2003. Rosenberg SA, Yang JC, Restifo NP: Cancer immunotherapy: Moving beyond current vaccines. Nat Med 10:909-915, 2004. Sarnaik AA, Weber JS: Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer J 15:169-173, 2009. Schadendorf D, Ugurel S, SchulerThurner B, et al: Dacarbazine (DTIC) ver-

sus vaccination with autologous peptidepulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: A randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 17:563-570, 2006. Viguier M, Lemaitre F, Verola O, et al: Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J�� Immunol 173:1444-1453, 2004. Dr. Sondak is Chair, Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, and Professor, Departments of Oncologic Sciences and Surgery, University of South Florida College of Medicine, Tampa, Florida.

Inside The ASCO Post – Don't miss these important perspectives: Page 1 Dr. Gabriel Hortobagyi offers his perspective on the recent recommendation by the Oncologic Drugs Advisory Committee (ODAC) that the breast cancer indication for bevacizumab be revoked. Page 3 Dr. Vernon Sondak discusses the role of vaccines in the treatment of melanoma patients and explores a new paradigm for treating melanoma patients with immunotherapy. Plus: Page 2 Dr. Wyndham Wilson and Dr. Joanne Mortimer offer their perspectives as voting members of ODAC about the Panel’s recent recommendation concerning bevacizumab in breast cancer. Page 6 Nine representatives of the breast cancer community speak about the role of bevacizumab in advanced breast cancer. Page 20 Direct from ASCO—Dr. Marilyn Heine discusses how oncologists need to advocate for their patients in the legislative arena as much as in the clinic. Page 28 Dr. Joseph Bailes answers questions about Medicare Drug Reimbursement and, in particular, emphasizes that all reimbursement issues pale in comparison to the lack of a solution for the sustainable growth rate problem.

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Copyright ©2010 by Harborside Press, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Domestic: $75 for the print or online edition; $125 for both editions. International: $125 for print or online edition; $175 for both editions. Contact subscriptions@harborsidepress.com.

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ASCOPost.com | SEPTEMBER 2010

PAGE 5

News Breast Cancer

Bevacizumab in Advanced Breast Cancer: FDA Committee Ruling Sparks Response from Oncology Community By Caroline Helwick

he oncology community was recently stirred with potentially practicechanging news: the 12-to-1 vote by the FDA’s Oncologic Drugs Advisory Committee (ODAC) to remove the advanced breast cancer indication for bevacizumab (Avastin). The Committee’s vote does not affect the current availability of the popular drug, but should the FDA follow ODAC’s recommendation—as is its usual practice—the management of many patients with breast cancer may change. Bevacizumab is currently approved in combination with paclitaxel for the firstline treatment of advanced HER2-negative breast cancer based on encouraging results of the E2100 trial.1 The FDA provisionally granted accelerated approval but requested confirmatory data, which Genentech supplied in November 2009 with the results of the AVADO and RIBBON-1 trials.2,3 On July 20, 2010, ODAC recommended against conversion to full approval.

impact [bevacizumab’s] approved uses for other cancer types.” In addition, the recommendation sparked mixed response from many in the

oncology community. In interviews with ODAC voting members (page 2), breast cancer specialists, oncologists in private practice, and a patient advocate (see

pages 6, 10, and 11), The ASCO Post captured initial reactions to the recommendation and its potential consequences.

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references on page 7

Recent Studies Fail to Confirm Degree of Improvement in PFS The panel concluded that bevacizumab plus commonly used chemotherapy (taxane or anthracycline-based, or capecitabine [Xeloda]) increased progression-free survival (PFS) but not overall survival (OS). They noted that the two recent studies failed to confirm the magnitude of PFS improvement seen in E2100—5.5 months (HR = 0.48; P < .0001). PFS was improved in AVADO by 0.09 months in combination with docetaxel (HR = 0.62; P = .0003); and in RIBBON-1 by 1.2 months in combination with taxane/anthracycline (HR = 0.64; P < .0001) and by 2.9 months in combination with capecitabine (HR = 0.69; P = .0002). In addition, the committee expressed concern about toxicity.

Mixed Response “We are disappointed by the committee’s recommendation and believe [bevacizumab] should continue to be an option for women with this incurable disease,” said Sandra Horning, MD, Senior Vice President and Global Head, Clinical Development Hematology/Oncology at Genentech. “We will continue to discuss the data from the more than 2,400 women who participated in three phase III studies with the FDA. This recommendation does not

Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11): 4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):64076415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

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Perspective Breast Cancer

Nine Members of the Oncology Community Speak Out about Bevacizumab’s Role in Metastatic Breast Cancer “There has not been a single metric by which the FDA has reviewed drugs for advanced breast cancer.”

ack in 2005, when we saw the E2100 data, we had great hopes that we were entering an era when a new class of drugs would be potent in advanced breast cancer. It’s fair to say that over the past 5 years, after five randomized controlled trials, the collective experience has suggested this Harold J. Burstein, MD drug is less impressive than we had hoped. That is a different statement than a regulatory “yes or no” question, but the recognition is that there may be less here than we first imagined. And though most breast cancer specialists believe bevacizumab (Avastin) is reasonably well tolerated, there are side effects and it is costly. The FDA is not charged with assigning costbenefit, but it is an unspoken though real issue when we are thinking about bevacizumab. On the other hand, we use lots of drugs that have not been shown to improve survival, such as ixabepilone (Ixempra) and capecitabine (Xeloda), which was approved based on response rate, and lapatinib (Tykerb), which was approved based on an increase in progression-free survival (PFS). Gemcitabine plus paclitaxel, however, was approved based on a survival benefit. This suggests there has not been a single metric by which the FDA has reviewed drugs for advanced breast cancer. In the wake of the recommendation from the Oncologic Drugs Advisory Committee (ODAC), the breast cancer community of researchers, patient advocates, pharmaceutical sponsors, NCI, and the FDA should come together to articulate what should be the accepted clinical trial endpoint, what should be the most important treatment goal, and what predicts for overall survival (OS) and for symptom relief or for a better experience for patients. For bevacizumab, or any other drug, we should shift away from “good or bad, yes or no.” —Harold J. Burstein, MD, Dana-Farber Cancer Institute and Associate Professor of Medicine, Harvard Medical School, Boston

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“It would be disappointing, though, to lose this agent [bevacizumab] from our armamentarium.”

he totality of evidence for first-line bevacizumab with chemotherapy supports an impact on PFS and a hint of a survival benefit, but the degree of benefit may be chemotherapy drug- and schedule-dependent. The concern is that if the FDA removes the current label, we may be throwing the baby out with the bathwater. That is, bevaciKathy S. Albain, MD, FACP zumab may work best when combined with metronomic or continuous, regular dosing of a chemotherapy agent— weekly paclitaxel as was used in E2100 (a 5.5-month prolongation of time to progression), or capecitabine (Xeloda), the strongest signal in RIBBON-1. It is possible this form of chemotherapy dosing is also antiangiogenic, so a combination with bevacizumab would modulate angiogenesis even more effectively. In contrast to E2100, the AVADO trial did not show a strong signal for bevacizumab added to every-3-week docetaxel, with a much shorter prolongation of response. So I choose a weekly taxane instead when selecting a bevacizumab regimen. And RIBBON-1 raised the concern that the placebo arm in the anthracycline/taxane (non-capecitabine) comparison performed slightly better than the bevacizumab arm, though not statistically significant. However, the capecitabine results were more encouraging. Therefore, the focus should be the weekly paclitaxel regimen as in E2100, which gave an amount of time free of progression that is meaningful to our patients. See page 11 for contributors’ disclosures of potential conflicts of interest.

When there is initial enthusiasm regarding benefit of a new agent, the FDA has taken a pragmatic approach in recent years. Accelerated approval is granted, with full approval pending rapid confirmation with similarly robust data in additional trials. This did not occur with AVADO and RIBBON-1, leading to a unanimous negative ODAC vote. It would be disappointing, though, to lose this agent from our armamentarium. An option could be to keep the label restricted as it is now and rapidly conduct a trial that duplicates E2100 (and possibly also the capecitabine arm of RIBBON-1), which could then lead to full approval. At the same time, further study is needed to demonstrate clinically meaningful efficacy of bevacizumab in combination with other common chemotherapy agents and regimens in the front-line setting. —Kathy S. Albain, MD, FACP, Professor of Medicine, and Director, Breast Research Program, Loyola University Chicago Stritch School of Medicine

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“I believe we have to set the bar high for cancer drugs, even in the metastatic setting.”

am as disappointed as anyone else to not see a survival benefit with bevacizumab, but I am willing to be honest about the fundamental implications of the data. I believe we have to set the bar high for cancer drugs, even in the metastatic setting. Patients expect survival advantages, and we should always try to produce this. In my view, Matthew Ellis, MB, BChir, PhD expensive drugs like bevacizumab that do not produce a survival benefit should be put aside to allow us to focus our energies on alternatives that may prove superior. Otherwise, our health-care dollars will be consumed by drugs that are not offering what our patients need. —Matthew Ellis, MB, BChir, PhD, Professor of Medicine, Chief of Medical Oncology, Washington University School of Medicine, St. Louis

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“If we only accepted cancer treatments that improve survival, we would severely limit options for our patients.”

was surprised and disappointed over the advisory panel recommendation since the three major clinical trials met their prespecified primary endpoint, PFS. The arguably simplistic view is that we want every new drug to give a statistically significant improvement in OS, but Edith A. Perez, MD the situation is more complicated than this, which merits careful consideration. If we only accepted cancer treatments that improve survival, we would severely limit options for our patients. For instance, in pancreatic cancer no agent improves survival, including gemcitabine, but this does not mean we don’t offer treatment to these patients. Turning to breast cancer, there are two regimens that have statistically improved OS, with data published in peer-reviewed journals and approved by the FDA (paclitaxel/gemcitabine and capecitabine/docetaxel), but we actually don’t use them very much. There are many treatments that have received regulatory agency approval for other endpoints outside of OS. An example is lapatinib’s approval with capecitabine in the refractory HER2 breast setting or in combination with letrozole as first-line treatment for patients with HER2-positive and ER-positive advanced breast cancer based on PFS. I feel that bevacizumab is perhaps being held to a higher standard than many other agents in the setting of advanced cancers. Many of the treatments currently used and reimbursed are lacking formal phase III comparisons showing that they improve continued on page 10

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Opinion

Bevacizumab, ODAC, and the FDA continued from page 1

somewhat different than what we have seen with a number of other drugs submitted for FDA approval. But what is also different is the interesting quirk we see in terms of adverse events and toxicity. They appear formidable on paper, yet the bulk of these events are hypertension and proteinuria, which are not only asymptomatic in most patients but are easily controlled. Testimony to this comes in the form of 800,000 patients exposed to this drug. Still, ODAC emphasized its potential for toxicity.

Unbiased Review?

this drug in the most unfavorable light. Additionally, there is some unfairness in the outcome in that Genentech was asked in 2008 to perform confirmatory trials that showed improvements in PFS without decrements in survival. Most reasonable observers would say Genentech satisfied this requirement. However, ODAC then questioned the clinical sig-

be differences of opinion from the various corners as to the requisite degree of benefit, by having this conversation we should arrive at what is commensurate with the expectations for advanced breast cancer and deliver something that patients would consider of value. —Gabriel Hortobagyi, MD M. D. Anderson Cancer Center, Houston

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There are thousands of ways to show you care: working to improve health is one of them.

From my perspective, the FDA reviewer’s presentation was disturbingly unfair. While the FDA must fulfill its function of protecting the public, decisions should be based on an unbiased review of the data. Such was not the case here. The reviewer noted, for example, that a hazard ratio for survival of 0.87 was not significant for bevacizumab. However, she suggested that a hazard ratio of 1.003 “favored the placebo” arm. It was a subtle use of language that, in my opinion, introduced bias against the drug. Similarly, while actual mortality was lower with bevacizumab, the reviewer concluded that drug-related mortality was higher—regardless of the potential for serious toxicities (cardiac complications, bowel perforations) to be attributable to the anthracycline or taxane components. I felt this conclusion was thoughtless, disingenuous, ignorant, or clearly biased, and it suggests the reviewer’s agenda was to paint

Sanofi-aventis U.S. is the U.S. affiliate of sanofi-aventis, a leading global pharmaceutical company that discovers, develops and distributes therapeutic solutions to help improve the lives of patients and their families. To find out more about our research, please visit www.sanofi-aventisoncology.com

Response from Oncology Community continued from page 5

References 1. Miller K, Wang M, Gralow J, et al: Paclitaxel plus bevacizumab versus paclitaxel for metastatic breast cancer. N Engl J Med 357:2666-2676, 2007. 2. Miles DW, Chan A, Dirix LY, et al: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28:3239-3247, 2010. 3. Robert NJ, Dieras V, Glaspy J, et al : RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer. J Clin Oncol 27(15S; abstract 1005), 2009.

nificance of findings, without providing a definition of such. A situation in which sponsors and investigators must guess at the FDA’s wishes is not transparent or predictable and is therefore unfair. There is an urgent need for the FDA and the cancer community to agree upon exactly what qualifies a drug for approval. Although there would certainly

The ASCO Post | SEPTEMBER 2010

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News

Bosutinib in CML continued from page 1

Chair of the CML Section, Department of Leukemia at M.D. Anderson Cancer Center in Houston. Noting that toxicity of bosutinib was acceptable in these studies, he commented, “Bosutinib is a contender for a major role in the treatment of CML.” Bosutinib is 30 times more potent than imatinib. This drug inhibits BCRABL signaling in CML cells and is active against all imatinib-resistant mutations, with the exception of the T315-I clone. Pfizer is sponsoring a phase III study of bosutinib as first-line therapy for patients with newly diagnosed chronicphase CML. The trial is currently accruing patients.

Second-line Therapy Dr. Cortes presented a multicenter phase I/II study in patients for whom prior imatinib therapy failed.1 Phase I was a dose-finding study that included 18 patients treated with bosutinib at 400, 500, or 600 mg/d. The phase II trial included 276 patients treated with bosutinib at 500 mg/d. The median age was 52 years, median time from diagnosis was 4 years, and patients had been on prior imatinib therapy for a median of 2.3 years. About 70% were imatinib-resistant, and 30% were imatinib-intolerant. At a median follow-up of almost 3 years, median duration of bosutinib therapy was 13.7 months. Three-quar-

ters of patients had dose interruptions, and 45% required dose reductions. The dose of bosutinib was escalated to 600 mg in 33 patients (22%). Of the 109 patients evaluable for best response, an overall response was seen in 102 (94%), and complete hematologic response was observed in 99 (91%). Of the 214 patients analyzed for cytogenetic response (CyR), a major CyR was observed in 136 (64%) and complete CyR was seen in 106 (50%). Of the 151 patients evaluated for molecular response, a major molecular response was seen in 79 patients (51%) and a complete molecular response was seen in 49 (32%). Response rates were higher in imatinib-intolerant patients than in imatinib-resistant patients. Time to achieve a major CyR was about 6 months, but responses continue to improve over time, Dr. Cortes said, and are continuing well into the second and third years of therapy. At 2 years, median progression-free survival (PFS) was 77% in imatinibresistant patients and 86% in imatinibintolerant patients. “The majority of patients are still alive,” Dr. Cortes said. Adverse events on treatment included diarrhea in 84% (grade 3/4, 9%), rash in 34% (grade 3/4, 9%), nausea in 44% (grade 3/4, 2%), and vomiting in 36% (grade 3/4, 3%). Fluid retention was uncommon, and pleural effusion occurred in 3%. The rates of grade 3 or 4 myelosuppression were as follows:

Bosutinib in Treatment-resistant CML ■■ Bosutinib was effective as second-line therapy for chronic myeloid leukemia in imatinib-resistant and –intolerant patients.

■■ A separate study showed efficacy for bosutinib as third-line therapy after first-line imatinib and second-line dasatinib had failed.

■■ The eventual role of bosutinib in CML will emerge from further studies.

Expert Point of View

n a separate interview, formal discussant of one of the bosutinib trials at ASCO, Michael J. Mauro, MD, Associate Professor, Center for Hematologic Malignancies at the Knight Cancer Institute at Oregon Health & Science University in Portland, offered this opinion: “Bosutinib clearly represents another option for patients with CML. With multiple agents in the running, optimizing treatment algorithms and sequencing of therapy in the face of resistance Michael J. Mauro, MD or intolerance will become increasingly important and potentially easier, as the goal is to find the right drug for each patient, to elicit or restore deep and long-lasting remission.” Dr. Mauro noted that choosing the optimal initial therapy might be the most important decision. “The bar is set the highest for the agent to be used at diagnosis. Thus, forthcoming data on the front-line use of bosutinib will be eagerly received but very carefully scrutinized, given the long track record of success with imatinib, the clear improvements made with nilotinib, and the ongoing challenge from dasatinib,” he stated.

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thrombocytopenia, 24%; neutropenia, 16%; and anemia, 12%.

Third-line Therapy A related poster focused on thirdline therapy with bosutinib.2 The poster, presented by Hanna J. Khoury, MD, Winship Cancer Institute at Emory University in Atlanta, showed that bosutinib was effective and well tolerated as third-line therapy in 90 patients with chronic-phase CML in whom both firstline imatinib and second-line dasatinib had failed. In imatinib- and dasatinibresistant patients, a complete CyR was reported in 6 (22%) of 27 evaluable patients, a complete hematologic response was reported in 18 (86%) of 21 evaluable patients, and a major molecular response was observed in 6 (27%) of 22 evaluable patients. Cytogenetic and molecular response rates were higher in the 23 patients who were on study due to intolerance to imatinib or dasatinib. The starting dose of bosutinib was

500 mg/d, with escalation to 600 mg if required. Median duration of treatment was 6.1 months in this ongoing phase II trial. Thus far, 3 patients have died and 14 have had disease progression. With a follow-up of 23 months, median overall survival was not reached in either resistant or intolerant patients. Responses were seen in patients with common BCR-ABL mutations, but not in those with T315I mutations.

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References 1. Cortes JE, Kantarjian H, Brummendorf T, et al: Safety and efficacy or bosutinib (SKI-606) in patients with chronic phase chronic myeloid leukemia following resistance or intolerance to imatinib. 2010 ASCO Annual Meeting. Abstract 6502. Presented June 7, 2010. 2. Khoury HJ, Kim D, Zaritskey A, et al: Safety and efficacy of third-line bosutinib in imatinib and dasatinib resistant or intolerant chronic phase chronic myeloid leukemia. 2010 ASCO Annual Meeting. Abstract 6514. Presented June 7, 2010

The ASCO Post | SEPTEMBER 2010

PAGE 10

Perspective

Nine Members of the Oncology Community Speak Out about Bevacizumab’s Role in Metastatic Breast Cancer Continued from page 6

OS, or even PFS or response rate. The concept of clinical benefit to the individual patient or in the context of public health is sometimes not easily quantifiable, although we use response, PFS, and even OS as surrogates for that endpoint. Based on the data that have been available for many months, the three first-line trials of bevacizumab in breast cancer met the prespecified endpoints of improving median PFS. I am concerned that if registration studies are designed with a prespecified endpoint, the endpoint is met, and then a committee recommends to regulatory agencies not to formally approve the agent for physicians to consider as an option for their patients, it would put into question how trials are designed. This scenario could be a disturbing lesson for patients who volunteer for studies, for nonprofit funding groups, and for pharmaceutical companies who might invest years and millions of dollars to develop a drug in an area of unmet need, satisfy the endpoint required for registration, and then have the drug rejected by the FDA. I hope the advisory panel recommendation will not be a setback for drug discovery. In addition, I respect the job that ODAC must perform, but I have to say that I was and remain concerned about the recent vote related to bevacizumab. I hope when the FDA meets later this year, they will vote at least to allow bevacizumab in combination with paclitaxel, and convert this regimen to full approval. In this case, their decision will not appear arbitrary but will be evidence-based. The FDA would come out a winner, and we would still have this regimen as an option for our patients. As a disclosure, I have received research grants from Genentech and have served in the capacity of uncompensated advisor. —Edith A. Perez, MD, Director Breast Cancer Program, Serene M. and Frances C. Durling Professor of Medicine, Mayo Clinic, Jacksonville

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“If a drug is expensive, relative to its benefits, then we need to develop a dialogue to address this issue.”

found it ironic that a representative of Genentech was in my office promoting bevacizumab for breast cancer the same day the FDA committee voted against it. It’s important for us as physicians to try to resolve these different spins on information. Right now, at Wilshire Oncology we use Cary Presant, MD, FACP bevacizumab plus a taxane as front-line treatment for metastatic disease in about 50% of patients. What I’ve been hoping for is the development of biomarkers of response to this drug, which would not only help us select appropriate patients for treatment but would also provide a subset of patients likely to demonstrate positive results in clinical trials of bevacizumab. Any future bevacizumab research should also focus on biomarkers. At ASCO this year, we heard encouraging data in other tumor sites. The addition of bevacizumab to standard regimens extended PFS by 3.8 months in ovarian cancer, and in gastric cancer the geographic subset of Pan-American patients experienced a 4.7-month gain in overall survival (though the larger population including European patients did not benefit). In the context of the recommendation in breast cancer, will the FDA look favorably on these findings? I would hope so, but this raises concern about the use of bevacizumab in other tumors. We are looking for leadership at the FDA to help sort out these differences. As a community physician, I want access to bevacizumab and any other drug that provides meaningful benefit. If it is expensive, relative to its benefits, then we need to develop a dialogue to address this issue. Perhaps manufacturers might be reimbursed proportionally to the benefit the drug provides, ie, have different payment schedules for bevacizumab in colon, breast, and lung cancers, where the magnitude of benefits varies. It’s a new approach, but without such innovations we may wind up with evi-

dence of varying benefits and lack of clinical access to the drugs with lesser benefits, and our ability to control disease will remain more limited. —Cary Presant, MD, FACP, Director of Medical Oncology, Wilshire Oncology Medical Group, Los Angeles, and Past President, Association of Community Cancer Centers

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“Bevacizumab may be a good drug for a subset, but it should not be on the market for all HER2negative patients until this is known.”

ince the ODAC vote, I’ve been monitoring the BCMets.org mailing list of over 1,000 women living with metastatic breast cancer. Although you would think their immediate reaction might be negative, instead it is decidedly mixed, based on patients’ personal experiAdvocate Musa Mayer ences with the drug’s activity, toxicities—and, of course, cost. There has been ambivalence about bevacizumab from the beginning. In my experience, patients do not necessarily argue just for more options, but for more beneficial options—drugs that are better than what we have now or at least provide a unique benefit. Many advocates believe OS should be the sole standard for drug approval, although OS is hard to prove due to crossovers and subsequent treatments, especially in the first-line setting. I do agree with ODAC that PFS is only a clinically meaningful endpoint when it represents a significant period of time, and when there is solid evidence that quality of life is not compromised. Some patients do well on bevacizumab, and others have a host of minor and major problems. Bevacizumab has significant toxicities, so it had better provide real benefit, and there is no good evidence of that. Some women do appear to have strong responses, maintained even when the chemotherapy agent is discontinued. Preliminary findings from post hoc analysis of E2100 suggest that tumors with different VEGF mutations respond differently. We hope that Genentech will take the ODAC recommendation as an incentive to start looking at this issue more urgently. Bevacizumab may turn out to be a good drug for a subset of patients, but it should not be on the market for all those with HER2-negative disease until this is known. And I have real concerns about subjecting patients with early breast cancer in adjuvant trials to a potentially toxic drug with minimal benefit. ODAC’s recommendation does show that the accelerated approval process works. Patient advocates were concerned that accelerated approval of bevacizumab would lead to an automatic full approval, despite problems with the drug. I was gratified to see that when confirmatory studies do not show meaningful clinical benefit, despite early promise, a drug can be removed from the market. —Musa Mayer, Breast Cancer Survivor, Patient Advocate, Author, Creator of AdvancedBC.org

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“My fear is that pharmaceutical companies will be discouraged from developing anticancer agents if they feel the bar they must jump over is simply too high.”

P Eric P. Winer, MD

ersonally, I was not expecting ODAC to recommend full approval of bevacizumab, but I was surprised that it recommended withdrawal of the indication. A number of drugs have been approved for breast cancer in recent years on the basis of mod-

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PAGE 11

Perspective

est benefit. “Modest benefit” does not mean that some patients don’t derive a more substantial benefit. Increasingly, however, many have wanted new drugs to show more benefit than older drugs, especially when treatment costs are high. The FDA is prohibited from considering cost, but society looks through a different lens—and this lens includes cost. My fear is that pharmaceutical companies will be discouraged from developing anticancer agents if they feel the bar they must jump over is simply too high. On the other hand, we don’t want to be in a situation where all that is being developed are drugs that add minimally to what we have. In truth, while PFS is probably a meaningful endpoint for some patients, ultimately our goal is to help patients live longer and better. If PFS doesn’t help them live longer, then the question becomes whether it helps them live better. I suspect that bevacizumab improves quality of life for some patients, but certainly not for all. Unfortunately, measuring quality of life is notoriously difficult. Although I believe there are subpopulations that get substantial benefit and do particularly well with bevacizumab, I don’t know how to select those patients. Perhaps we will sort this question out in the adjuvant trials. It does seem that the FDA is sending a message to the oncology community, a message that drug approval in the future may look different than it has in the past. We will have to think carefully about drug development, and in this era of increasingly targeted therapies, it is our responsibility to identify populations that will benefit the most from new agents. —Eric P. Winer, MD, Director of the Breast Oncology Center at Dana-Farber Cancer Institute and Professor of Medicine, Harvard Medical School, Boston

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“I think it unfortunate that insurance companies (including Medicare) have taken FDA approval as an indication of good medical practice.”

he details upon which ODAC based its decision are obvious: First and foremost, bevacizumab does not prolong OS. But clearly there is biologic activity, perhaps a positive interaction with weekly pacliSteven E. Vogl, MD taxel. I wish the system would let us give drugs the way we think they should be given, which in my practice tends to be with weekly paclitaxel. Maybe because of how I give bevacizumab, I usually get results like those in E2100. The first patient I treated had a 2-year remission and excellent quality of life. Another had liver metastases disappear on MRI and has had a 7-month remission. Another patient is a 40-year-old with terrible organ disease, including liver and CNS metastases. I started her on the drug in March 2009 and she is still doing great. Now she asks me, ‘What will happen to me if the FDA takes [bevacizumab] away?’ While I could prescribe bevacizumab off-label, the price of the drug is unconscionable. I think it unfortunate that insurance companies (including Medicare) have taken FDA approval as an indication of good medical practice, especially since the FDA tends to weigh one thing above the other in fairly arbitrary bureaucratic ways. The FDA review is a legally mandated adversary proceeding in which the drug company seeks approval and the FDA seeks evidence that the medication is both safe and effective. The FDA is not charged to, nor is it equipped to, set standards of medical care. Its job is to control marketing claims and protect consumers against dangerous drugs. Input from both patients and payers should be heard in open proceedings independent of the FDA review, which is, of necessity, very detailed and technical. Such sessions, in which patient benefit is a major concern, are needed to help arrive at a fair evaluation of medical practice and what should be covered. —Steven E. Vogl, MD, Private Practice, Bronx, NY

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“The crux of the issue is whether overall survival should be the primary endpoint…though a survival benefit is increasingly hard to show.”

2100 demonstrated several months’ increase in PFS with the addition of bevacizumab, while PFS benefit was smaller in subsequent trials and an OS benefit was not shown. In some ways I can understand, therefore, where the FDA advisory committee was Sandra M. Swain, MD coming from in its recommendation. However, the primary endpoint of the studies was PFS, and in all three studies, PFS was statistically significantly improved. From this standpoint, bevacizumab should be approved, if this was the agreement with the FDA. There is the more global picture, however, that we want our patients to actually survive longer. These studies bring up a major point; in fact, it is the crux of the issue, but it was not fully addressed at the hearing: whether OS should be the primary endpoint in metastatic breast cancer. Unfortunately, it is increasingly hard to show a survival benefit in a population that is living a median of at least 2 years now. One of the few positive trials in this regard was with trastuzumab (Herceptin), which is an extremely effective drug that has a definite target. If there is a survival benefit with bevacizumab, obviously it is not that large, at least in an unselected population. We need better drugs, we need targeted drugs, and we need to understand the subset for which they are effective. There are definitely many patients who can benefit from bevacizumab—that has been shown in the data—but we have to learn how to identify them. I can see no reason to stop the adjuvant trials with bevacizumab. The agent clearly has activity in breast cancer, as shown by the increased response rate and PFS benefit. —Sandra M. Swain, MD, Medical Director, Washington Cancer Institute, Washington, DC

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Compiled and reported by Caroline Helwick. Editor’s Note: FDA indicated it is the Agency’s policy not to comment on ODAC’s recommendations. The Agency will make a decision about whether to revoke the breast cancer indication later in the year. See page 2 for perspectives from ODAC voting members Wyndham Wilson, MD, and Joanne Mortimer, MD. Watch for further coverage in The ASCO Post.

Disclosure of Potential Conflicts of Interest Harold J. Burstein, MD: Dr. Burstein has no financial interest or other relationship with the manufacturers of any products discussed in this report. Kathy S. Albain, MD, FACP: Dr. Albain has disclosed: Attending a one-time advisory board meeting for Genentech (compensated) and a one-time advisory board meeting for Roche (compensated), pertaining to their pipeline but not dealing with bevacizumab. Matthew Ellis, MB, BCHir, PhD: Dr. Ellis has disclosed: Consultant, Genentech (<$10,000); Consultant, Roche (<$10,000) Edith A. Perez, MD: Dr. Perez has disclosed: Research grants, Genentech; Advisor, Genentech (uncompensated). Cary Presant, MD, FACP: Dr. Presant has disclosed: Research funding (Genentech, Roche, DiaTech Oncology); Consultant/ advisor (Genentech). Musa Mayer: Ms. Mayer has disclosed: Consultant for programs supported by Genentech (uncompensated). Eric P. Winer, MD: Dr. Winer has disclosed: Principal investigator for a Genentech-sponsored trial at Dana-Farber Cancer Institute. Steven E. Vogl, MD: Dr. Vogl has no financial interest or other relationship with the manufacturers of any products discussed in this report. Sandra M. Swain, MD: Dr. Swain has disclosed: Research funding, Genentech; Advisory Board, Genentech/Roche (uncompensated).

With the ﬁrst and only IV mTOR inhibitor indicated for advanced renal cell carcinoma (RCC)1...

Change

expectations

for overall survival

Important portant Safety Information • TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild hepatic impairment (bilirubin >1–1.5 x ULN or AST >ULN but bilirubin ≤ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin >1.5 x ULN. • Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. • Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL. – The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively. • The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections. • Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics. • Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. • Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. • Due to abnormal wound healing, use TORISEL with caution in the perioperative period. • Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.

TORISEL—Significant overall survival benefit as first-line therapy1 Kaplan-Meier curves for overall survival (OS)*—TORISEL vs IFN 1

Results from a phase 3, multicenter, 3-arm, randomized, open-label study conducted in 626 previously untreated patients with advanced RCC.1

• Studied first-line in patients with ≥3 of 6 preselected prognostic risk factors1

The advanced RCC pivotal study included patients with2 • Clear-cell or non–clear-cell tumor histologyII • Any nephrectomy status

mTOR=mammalian target of rapamycin. IFN =interferon alpha. CI=confidence interval. * Time from randomization to death.1 † A comparison is considered statistically significant if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths).1 ‡ Based on log-rank test stratified by prior nephrectomy and region.1 § Based on Cox proportional hazard model stratified by prior nephrectomy and region.1 II 82% and 82.5% of patients had known clear-cell histology for TORISEL and IFN , respectively.2 ¶ NCCN Category 1 recommendations are based on high-level evidence (eg, randomized controlled trials) and uniform NCCN consensus.3 # TORISEL was approved by the FDA in 2007.1

• Category 1 NCCN recommendation— first-line for poor-prognosis patients3¶ • >3 years experience since FDA approval#

Median duration of treatment was 17 weeks (range 1-126 weeks) for the TORISEL arm and 8 weeks (range 1-124 weeks) for the IFN arm.1

• Live vaccinations and close contact with those who received live vaccines should be avoided. • Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped. • The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%). • In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every 2 weeks. Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion. • Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%). • Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended. • St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided. • The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see the brief summary of the full Prescribing Information on the next page. References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. Data on file, Pfizer Inc. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2010.

Change expectations

The ASCO Post | SEPTEMBER 2010

PAGE 16

News Head & Neck Cancer

Zalutumumab Improved PFS in Squamous Cell Head and Neck Cancer, But Questions Remain about Drug’s True Value By Alice Goodman

alutumumab significantly improved progression-free survival (PFS) and disease control (response plus stable disease) compared with best supportive care in patients with advanced squamous cell carcinoma of the head and neck in whom standard platinum-based chemotherapy had failed.1 The investigational drug improved overall survival (OS) compared with best supportive care, but the difference was not statistically significant.

Jean-Pascal Machiels, MD, PhD

“ZALUTE is the first controlled study to show an EGFR antibody induces clinically meaningful improvement in progression-free survival,” said lead author Jean-Pascal Machiels, MD, PhD, of Cliniques Universitaires Saint-Luc-Université Catholique de Louvain, Belgium, at the 2010 ASCO Annual Meeting. Zalutumumab, a fully humanized, high affinity monoclonal antibody targeted to epidermal growth factor receptor (EGFR), is under development by Genmab in Denmark. The drug has been

awarded Fast Track status by the FDA for head and neck cancer patients in whom standard therapies have previously failed.

Study Details The open-label, parallel-group, phase III ZALUTE trial randomly assigned 286 patients with SCCHN to receive best supportive care plus the option to use methotrexate (n = 95) vs zalutumumab plus best supportive care and no methotrexate (n = 191). Imaging was performed every 8 weeks for assessment of treatment response. Baseline characteristics were well balanced between treatment arms. Mean age was about 57 (range, 28–80). About 88% were males, and about 82% had an ECOG performance status of 0. Median duration of squamous cell carcinoma of the head and neck was about 19 weeks at entry to the trial. About two-thirds had distant metastasis. About 40% received prior radiation, and about 55% underwent surgery. About 40% had concurrent chemoradiation therapy, 16% had induction chemotherapy, and 83% had been treated with palliative chemotherapy. Dr. Machiels explained that zalutumumab was titrated to grade 2 rash to obtain maximal efficacy (as rash is associated with efficacy). The monoclonal antibody was given once a week, and patients were treated until disease progression. The dose was increased by 4 mg/kg every 2 weeks until the appearance of rash.

Zalutumumab in Head and Neck Cancer ■■ Zalutumumab improved progression-free survival and disease control vs best supportive care in advanced squamous cell carcinoma of the head and neck after platinum-based chemotherapy has failed.

■■ Survival was not statistically different with zalutumumab. ■■ The cost of this EGFR inhibitor would equal approximately $709,000 per year of life gained.

w! e N Visit The ASCO Post website at:

ASCOPost.com

Expert Point of View

espite the positive results of ZALUTE, formal discussant of this trial at the ASCO Annual Meeting, Alexander D. Colevas, MD, does not think this drug will find a role in clinical practice. Dr. Colevas is an oncologist at Stanford University Cancer Center, Head and Neck Division, Palo Alto, California. As the first randomized, controlled trial of EGFR inhibitor monotherapy in this setting, ZALUTE is worthy of note, Dr. Colevas commented. This study compared zalutumumab vs best supportive care plus methotrexate, and most patients got methotrexate “right out of the gate,” he said. But he questioned the use of methotrexate as the control arm. “Is best supportive care plus methotrexate what oncologists are really doing? Most of us don’t reach for methotrexate in platinum failure,” he explained. Even though there was a 1.5-week difference in median survival in this trial, Dr. Colevas said that it is not clear that patients’ quality of life is better on this drug. The slight separation of the overall survival curve favoring zalutumumab is “interesting, not definitive,” he noted. Regarding the astronomic costs of new EGFR inhibitors, by his “back of the envelope” calculations, the drug would cost approximately $709,000 per year of life gained. “This is not particularly cost-effective,” he commented. “Will we go home and do things differently with EGFR inhibitors in [squamous cell carcinoma of the head and neck]? I am not going to. Despite the hype, is there a meaningful difference with these new drugs?… I don’t advocate larger trials of these agents. I think we would gain more from exploring new and different targets,” he stated.

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Zalutumumab did not significantly improve OS: Median OS was 5.2 months for the control arm vs 6.7 months in the zalutumumab arm. Six-month OS was 42% in the control arm vs 57% in the zalutumumab arm. PFS was significantly better in the zalutumumab arm (P = .0010). Median PFS was 8.4 weeks vs 9.9 weeks, respectively. The 26-week PFS was 7.3% in the control arm vs 20% in the zalutumumab arm. PFS was consistently improved by zalutumumab in all subgroups, including age, sex, performance status, location of primary tumor, distant metastasis, duration of disease, and EGFR expression. Disease control was achieved in 48% vs 72%, respectively. Adverse events (all grades) more frequently occurring with the monoclonal

antibody included skin rash (92% vs 0% in the control arm), anemia (25% vs 19%), pyrexia See page 43 (22% vs 13%), headache (17% vs 6%), weight loss (16% vs 9%), diarrhea (13% vs 4%), and hypomagnesemia (12% vs 2%).

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Reference 1. Machiels J-P, Subramanian S, Ruzsa A, et al: An open-label, randomized, phase III trial of zalutumumab, a human monoclonal EGF receptor antibody, versus best supportive care, in patients with noncurable squamous cell carcinoma (SCCHN) of the head and neck who have failed platinum-based chemotherapy (ZALUTE). 2010 ASCO Annual Meeting. Abstract LBA5506. Presented June 7, 2010.

ASCOPost.com | SEPTEMBER 2010

PAGE 17

Appointments

Craig Thompson Named President of MSKCC Craig B. Thompson, MD, has been named the new President and Chief Executive Officer of Memorial SloanKettering Cancer Center (MSKCC) effective November 2, 2010. He succeeds Harold Varmus, MD, who is now Director of the National Cancer Institute.

Rocky Mountain region’s only National Cancer Institute-designated comprehensive cancer center. “By directing an NCI–designated comprehensive cancer center, I can contribute broadly in a way I’ve not been able to before,” said Dr. Theodorescu. Dr. Theodorescu was recruited from his post as Director of the Mel-

lon Urologic Cancer Institute at the University of Virginia. As a bladder cancer expert, he focused his research on looking for biomarkers and new drugs that can lead to customized, targeted treatments for patients with bladder cancer. Dr. Theodorescu has indicated his top priorities at UCCC will include:

Identifying genes that drive cancer to metastasis; cancer stem cell and regenerative medicine research and engineering; personalized medicine for predicting cancer outcome as well as response to therapy; and promoting the early phase clinical trials program at UCCC. continued on page 34

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CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial Craig Thompson, MD

Dr. Thompson has served as Director of the Abramson Cancer Center at the University of Pennsylvania and Associate Vice President for Cancer Services of the University of Pennsylvania Health System since 2006. “We are at a time when transformative developments in biomedical research are greatly expanding opportunities to understand disease and to improve human health,” said Dr. Thompson. “I look forward to building on MSKCC’s achievements and tradition of excellence and to working with my colleagues here in making progress in controlling and ultimately curing cancer.” Dr. Thompson attended Dartmouth College and completed his studies at Dartmouth Medical School. He received his MD degree from the University of Pennsylvania and completed his residency at Harvard’s Peter Bent Brigham Hospital. Dr. Thompson’s current research focuses on the role that metabolic changes play in the origin and progression of cancer.

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UCCC Names New Director Dan Theodorescu The University of Colorado Cancer Center (UCCC) has appointed Dan Theodorescu, MD, PhD, as the new Director of the UCCC consortium, effective July 1, 2010. Dr. Theodorescu follows interim director Dr. Tim Byers, Associate Dean of the Colorado School of Public Health. Dr. Theodorescu holds the Paul Bunn Chair in Cancer Research, named after the lung cancer pioneer who in 1988 founded UCCC, the

A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

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Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

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The ASCO Post | SEPTEMBER 2010

PAGE 18

Direct from ASCO

2011 Diversity in Oncology Initiative Awards - Applications Opening Soon Due Dates: December 16 (LRP) and January 31 (MSR and RTA)

he ASCO Cancer Foundation will soon begin accepting applications for three types of awards created by the ASCO Diversity in Oncology Initiative and funded by Susan G. Komen for the Cure®. The awards support the program’s goals of addressing the lack of diversity in the oncology workforce and obstacles to oncology care in underserved communities. Applications for the Loan Repayment Program will open on September 16. Applications for the Medical Student Rotation and Resident Travel Award will open on October 31.

Medical Student Rotation Award The Medical Student Rotation Award provides an 8- to 10-week clinical or research oncology rotation for U.S. medical students from underrepresented populations. Applicants must be enrolled in a U.S. allopathic or osteopathic medical school and be from an underrepresented population as defined by the eligibility criteria. Recipients are paired with a mentor who provides ongoing academic and career guidance. Each medical student receives a $5,000 stipend for the rotation plus $1,500 for future travel to the ASCO Annual Meeting. The student’s mentor receives $2,000. Amanda Adeleye, one of six medical students who received a Medical Student Rotation Award in 2010, was a first-year student at Columbia when she applied. The award allows the student to

choose a mentor, so Ms. Adeleye picked Vincent L. Cryns, MD, of Northwestern University, a cancer researcher with whom she had worked for a summer after her freshman year in college. Cryns directs the physician scientist training program at the Feinberg School of Medicine and also sees patients with breast cancer in a clinic at the SUCCEED Breast Cancer Survivorship Program. Ms. Adeleye reports that during her rotation she “did a mix of research in the lab and seeing patients for 2 days each week.” She says that one of her most significant experiences during the rotation was a patient visit she participated in. “We met a woman who had been diagnosed with breast cancer a few days earlier. It was a quiet, powerful, humbling experience just to be there when someone is beginning to fight the fight of her life.” Adeleye plans a career in academic oncology.

Resident Travel Award The Resident Travel Award provides financial support for residents from underrepresented populations to attend the ASCO Annual Meeting. Applicants must be residents in an ACGME-accredited residency program and must demonstrate an interest in pursuing oncology as a career. The award includes complimentary meeting registration and a $1,500 travel advance. Frank Akwaa, MD, was one of 13 award recipients who received a Resident Travel Award and attended the

2010 Annual Meeting in Chicago. He was in his final residency year at Johns Hopkins at that time and has recently started his oncology fellowship at the University of Rochester. Dr. Akwaa had never attended the ASCO Annual Meeting before and says, “It was a great experience for me. Next time I go I’ll know how to navigate it.” He explained that mentors assigned as part of the award suggested sessions to attend and says, “I went to all of them and was glad I did.” Dr. Akwaa’s advice to future applicants is “if you have the opportunity, jump on it. It’s a once-in-a-lifetime opportunity. I learned so much about current research and what options there are for careers in oncology.”

Loan Repayment Program The Loan Repayment Program provides repayment of qualifying educational debt to oncologists or oncology fellows who commit to practicing oncology in a medically underserved region of the United States (as designated by the U.S. Health Resources and Services Administration as a Health Professional Shortage Area or Medically Underserved Area). Applicants must be an Associate or Active ASCO member or submit a membership application with the award application. The program will repay up to $35,000 per year for 2 years (up to $70,000 total) of qualifying education debt.

How to Apply For application forms and complete application criteria for all three awards, visit The ASCO Cancer Foundation website at www. ascocancerfoundation.org and click on “Awards.”

Brooke Gillett, DO, was among three physicians who received an award in the Loan Repayment Program. After completing her fellowship at the University of Utah in Salt Lake City, Gillett joined Oncology Hematology Associates in Springfield, Missouri. She had decided she wanted to practice in a smaller community before she saw a poster about the ASCO Loan Repayment Program in the fellowship office. “I wanted to live in a smaller community, I wanted to be busy, and I love going where I’m really needed and it will be really fulfilling.” Her practice serves patients in all of southern Missouri and in northern Arkansas. She says that without access to oncology care in Springfield, patients would have to drive 6 hours to St. Louis.

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ASCO Members Have Advance Access to Hotels for 2011 Annual Meeting ASCO Housing Block Opens to Members in September

s an exclusive member benefit, ASCO members have advance access to secure housing for the 2011 Annual Meeting 2 months prior to the general public. Members are encouraged to take advantage of this benefit, as experience from previous meetings shows that highly soughtafter hotels fill up within hours of the opening of housing and registration. In late September, ASCO members can visit the Annual Meeting housing and registration website (www.asco.org/chicago2011) to select their hotel for the meeting, June

3–7 in Chicago. An up-to-date inventory of available hotel rooms, descriptions of each hotel, and the distance to the convention center are provided online. Reservations may be changed or canceled without a fee if the change is made prior to a specified date listed online or on the housing confirmation. Hotel reservations may be made without registering for the meeting at the same time, but both processes are linked for easy navigation.

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June 3-7, 2011 McCormick Place, Chicago To reserve hotel space: www.asco.org/chicago2011 To become an ASCO member: www.asco.org/ASCOv2/Join+ASCO/Become+a+Member

ASCOPost.com | SEPTEMBER 2010

PAGE 19

Direct from ASCO

ASCO and Advocates: Partners in Patient Advocacy

SCO and ASCO members work hand-in-hand with patient advocates to address a wide array of issues affecting people with cancer, including the advancement of cancer research, legislative and regulatory matters related to cancer care and research, improving the quality of cancer care, raising public awareness of the disease, and providing support to those living with cancer. Whether advocates are operating from an individual or organizational level, locally or nationally, ASCO supports their efforts and offers opportunities and resources to promote all types of advocacy for people with cancer. Independent of their particular focus, patient advocates share a common goal with ASCO: addressing the needs and concerns of people with cancer and ultimately accelerating progress against cancer.

services, and resources to the professional oncology community. As an added benefit, ASCO meetings are great places for advocates to network with one another as well as with oncology professionals. ASCO’s Annual Meeting Patient Advocate Programs have developed significantly over the past 7 years to reflect the Society’s commitment

ganizations exhibit at each ASCO Annual Meeting. Beyond exhibit opportunities, programs offered for advocates at ASCO’s Annual Meeting include: ■■ A teleconference for patient advocates that takes place in midMay, highlighting studies that will be presented at the meeting and answering advocates’ ques-

to working with the advocacy community. Approximately 350 patient advocates attended the 2010 ASCO Annual Meeting, representing well over 100 patient advocacy organizations. Twenty organizations exhibited in the ASCO-sponsored Patient Advocacy Booth, prominently situated at the front of the Oncology Professionals Hall. Established in 1992, this booth allows organizations to promote their mission and programs to meeting attendees. In addition, about 30 other patient advocacy or-

tions related to the research ■■ Discounted registration rate ■■ Discounted subscription to A SCO’s Virtual Meeting and Podcast ■■ Research Review Sessions, during which ASCO members review disease-specific topics presented at the meeting, explain how the research is relevant to patients, and answer questions ■■ Patient advocate scholarships, made possible by The ASCO Cancer Foundation ■■ A lounge for patient advocates

ASCO Programs for Patient Advocates ASCO’s mission has always centered on improving the treatment and care of people living with cancer. This mission includes serving not only the educational needs of the professional oncology community, but also the educational needs of the patient and survivor communities as well. As such, ASCO provides the opportunity for advocates to attend the ASCO Annual Meeting and ASCO Symposia to gain the education, knowledge, and skills necessary to participate in the cancer research process. ASCO meetings also enable advocacy organizations to promote their programs,

ASCO Resources for Patient Advocates One of ASCO’s shared goals with the patient advocacy community is to increase the accessibility of accurate and current information to people living with cancer. ASCO’s doctor-approved patient information website, Cancer. Net, includes a section dedicated to Advocacy and Policy. Here, visitors can learn about ASCO’s programs for patient advocates, read about what it means to be a cancer advocate, find information about current policy issues, and learn how to effectively communicate with elected officials. A comprehensive section lists Cancer-Specific Resources—national, not-for-profit organizations that provide additional information, services, and support. The Cancer News and Meetings section includes easy-to-read summaries that put top scientific news from ASCO meetings into context for patients. Videos and podcasts with national and international cancer experts are included as well, breaking down the science into specific disease areas and explaining what the studies mean for people with cancer. These and other resources are freely available on Cancer.Net. Additional information about ASCO’s patient advocate programs can be obtained by contacting patientadvocates@asco.org.

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Save the Date December 9-11, 2010 Chicago Chicago Multidisciplinary Symposium in Thoracic Oncology www.astro.org/Meetings

January 20-22, 2011 San Francisco Gastrointestinal Cancers Symposium www.gicasymposium.org

February 17-19, 2011 Orlando, Florida Genitourinary Cancers Symposium www.gucasymposium.org

The ASCO Post | SEPTEMBER 2010

PAGE 20

Direct from ASCO

Oncologist Urges Political Advocacy at Grass Roots Level

edicare reimbursement. Medical liability reform. Stem cell research. Insurance coverage for investigative drugs. These are but a few examples of the hundreds of areas in which legislation and regu-

lations affect medical practice and patient care. Marilyn Heine, MD, a member of Regional Hematology Oncology Associates in Langhorne, Pennsylvania, thinks that physicians can

make a difference in public policy and have a responsibility to do so. “I firmly believe that just as we advocate for our patients in the clinical arena, it’s imperative that we advocate for them in the legislative

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Marilyn Heine, MD

arena,” she said. Dr. Heine practices what she preaches. She is the coordinator of a physician advisory group that communicates regularly with their congressman, Patrick Murphy. She organized the group years ago at the request of a member of the U.S. House of Representatives on whose campaign she had worked. His successors were aware of this resource and have continued to use it.

Education, Rapport Important Legislators want help in understanding the implications of health-care policies, according to Dr. Heine. “The essential thing in advocacy is education. Just as we educate our patients about the best treatment for them, we can educate our policymakers on what would be the best position for them to take to benefit their constituency. The vignettes we provide about our patients and how issues affect them put a face on these issues.” An occasional message to legislators is not as effective as developing an ongoing relationship, Dr. Heine noted. She suggests getting to know lawmakers’ senior staff in their home office as well as their legislative aides in Washington. One activity that she found very productive was hosting a tour of her oncology practice. “We described the activities in the different areas where we provide care and the many support services provided daily, most of which are uncompensated,” Dr. Heine reported. She commented that this exposure to a real practice with real patients helped illustrate how Medicare payments are already falling short of the cost of care of oncology patients.

ASCOPost.com | SEPTEMBER 2010

PAGE 21

Direct from ASCO Tips and Tools for Political Advocacy Dr. Heine has several suggestions for oncologists interested in developing a dialog with members of Congress. One is to engage in the legislator’s campaign. “Volunteer, contribute, and encourage others to support the candidate. If you are interested, host a fundraiser or a ‘meet and greet,’” she said. To arrange a meeting or to host the legislator at your practice, call the legislator’s scheduler. Dr. Heine cautioned that you have to be de-

termined—it often takes more than one call. But, she noted, perseverance pays off. “I have seen positive results, such as a member of Congress modifying his position and becoming a champion of a bill,” she said. “Last year, Representative Patrick Murphy sent a ‘Dear Colleague’ letter to other members of the House, urging passage of the bill to reform the Medicare sustainable growth rate payment system for physicians. In another instance, I was fortunate in securing a congressionally autho-

rized research grant.” Dr. Heine also encouraged using ASCO resources. She has found the ASCO staff and online tools to be extremely helpful in her advocacy efforts. “ASCO provides updates on issues and excellent talking points that help you formulate an agenda,” she noted. For oncologists interested in becoming a public policy advocate she suggested joining ASCO’s Advocacy Network at http://capwiz. com/asco/home. Finally, Dr. Heine noted that pro-

moting public and patient awareness of issues can help move the policy agenda. She writes letters to the editor of both the local paper and the Philadelphia Inquirer, and her office has information available in the waiting room for patients interested in advocating access to care and other issues. Dr. Heine said, “As physicians, we have a unique role in advancing the advocacy agenda for cancer care issues.”

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First-of-its-kind Symposium Focuses on Solutions to Obstacles in Clinical Trial Accrual Event Cosponsored by ASCO and the National Cancer Institute Successful Strategies Presented

Neal J. Meropol, MD

hat strategies work effectively in reaching full enrollment in clinical trials? That was the question addressed at a 1½-day symposium held in Bethesda, Maryland, last April. With a limit of 300 participants, many who wanted to attend had to be turned away. “There was tremendous enthusiasm for the conference among investigators at both academic medical centers and community sites,” said Neal J. Meropol, MD, from University Hospitals Case Medical Center and Case Western Reserve University, one of four cochairs of the event. The “launch pad” for the NCIASCO Cancer Trial Accrual Symposium: Science and Solutions, according to Dr. Meropol, was the premise that everyone understands what the barriers are. With that as the foundation, the symposium focused on empirical research that had tested ways to overcome obstacles to clinical trial enrollment. “This was the first national meeting in which the explicit focus was on solutions to barriers in clinical trial recruitment,” he pointed out.

Representatives from sites actively engaged in clinical trial recruitment presented research and interventions that had enhanced accrual among a variety of patient populations and types of trials. In breakout sessions, research was presented about specific aspects of accrual, such as recruitment planning, community outreach, leadership, organizational culture, and minority recruitment. “I was excited to see some of the successes that organizations had by using strategies with doctors as well as patients,” Dr. Meropol said. As an example, a three-pronged approach used successfully at Ohio State University Comprehensive Cancer Center (OSUCCC) involved interventions with patients and family members, referring physicians, and the faculty and staff of the cancer center. During the 4-year period 2004-2007, accruals to therapeutic clinical trials had stagnated at about 700 accruals each year. To counter this, OSUCCC developed a campaign called “2010 by 2010” with the ambitious goal of enrolling 2,010 patients during the year 2010. Using a variety of strategies, including staff and faculty training, new communication methods with patients and referring physicians, and revised management systems in the Clinical Trials Office, annual patient accrual at OSUCCC has already increased 69% and is on track

to exceed its goal for the year 2010 by 695 patients. Commenting on the OSUCCC experience, which was one of four presented in a plenary session at the symposium, Dr. Meropol said, “The notion that institutional culture plays a big role in accrual success really resonated with the participants at the symposium.” He identified several take-home messages that emerged at the symposium: ■■ Site-specific applicability: Some interventions are more appropriate and effective in the community, whereas others work better in academic medical centers. ■■ Awareness: Any steps that improve awareness about clinical trials among communities, physicians, and patients can be useful. ■■ Organizational culture: Any changes to institutional culture that promote the importance of clinical trials among stakeholders at all levels can be helpful. ■■ Infrastructure: Basic changes in clinical trial infrastructure are needed to decrease impediments to physicians and patients to participate in clinical trials. Such infrastructure changes may include increased reimbursement to cover administrative costs of participation, wider insurance coverage for patients, and reduction in regulatory and paperwork requirements.

■■ Recruitment planning: In planning a clinical trial, more attention should be given to developing recruitment strategies and making sure that eligibility requirements are applicable to the patients seen in routine practice. Dr. Meropol noted that funding for clinical trials was not addressed, in that it was outside the scope of the symposium.

Disseminating Results and Next Steps A report summarizing the findings of the meeting is being prepared for submission to a cancer-related journal, Dr. Meropol stated. The document will incorporate literature references for the reader to refer to in developing accrual strategies. The success of the symposium has also generated enthusiasm for having similar meetings in the future, perhaps every other year. One of the goals of the meeting was to identify recommendations for future research about accrual. To that end, each breakout group identified specific topics related to clinical trial accrual for which more research is needed. The report of the symposium will include recommendations for a research agenda related to clinical trial recruitment. Slides presented at the meeting can be viewed on ASCO’s website at www. university.asco.org/CT2010.

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ASCOPost.com | SEPTEMBER 2010

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Special Feature Lung Cancer

Targeting EGFR in Lung Cancer in 2010 Studies are better defining mutations and evaluating strategies for tackling resistance. By Caroline Helwick

he epidermal growth factor receptor (EGFR) is dysregulated by a variety of mechanisms in non–small cell lung cancer (NSCLC). Drugs that target EGFR, therefore, have become an integral component of care, although their optimal use is still being refined. Two experts in this area addressed some of the relevant clinical conundrums, at an Education Session held at the 2010 ASCO Annual Meeting. Tony Mok, MD, Professor of Oncology at the Chinese University of Hong Kong, said randomized studies have established the key driver of response to EGFR-targeted therapy to be the activating EGFR mutations, not Asian ethnicity. In the pivotal Iressa Pan-Asia Study,1 response rates to gefitinib (Iressa) were 71% for patients with mutations compared to 1% for those without. Perhaps as importantly, Dr. Mok added, the Pan-Asia study showed that for treatment-naive patients, chemotherapy is superior to a tyrosine kinase inhibitor (TKI) in the absence of EGFR mutations.

pooled analysis of 1,809 patients, however, found median PFS to be 13.2 months with erlotinib (Tarceva) and 9.8 months with gefitinib (5.9 months with chemotherapy),6 offering a “suggestion” of enhanced benefit with erlotinib, but further studies are needed, according to Dr. Mok.

Treating Beyond Progression Research is focusing on better understanding mechanisms of resistance to TKIs and strategies to overcome them, said David M. Jackman, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston. Dr. Jackman noted that when TKIs are stopped, patients could have worsening of disease. Therefore, progression should be measured while the patient is on treatment. “We don’t want to misinterpret radiologic worsening as tumor progression related to resistance. It might just be, for example, because the drug was held for treatment of a rash,” he pointed out. Similarly, progression in the central nervous system may not represent

We have to select patients for their biomarkers before putting them on an EGFR TKI in the first-line setting... – Tony Mok, MD

“This study informed us that we have to select patients for their biomarkers before putting them on an EGFR TKI in the first-line setting,” he noted. Emerging data would suggest that the exon 19 deletion may be more predictive of response to EGFR TKIs than exon 21 mutation, as this group has better response rates and progressionfree survival (PFS),2,3 although a recent study found no differences.4 Zeroing in on the mutations would help define candidates for anti-EGFR treatments. The Japanese NEJGSG002 study,5 the WJTOG3405 study,4 and the Spanish Lung Cancer Group trial3 confirmed the benefits of TKIs in patients with EGFR mutations, but no large comparative study has established the superiority of one agent over the other, he added. A recent

a genetic change associated with resistance, but rather, insufficient penetration of drug into a sanctuary site. In this case, increasing the dose may achieve the proper concentration. “We have induced cytologic clearance of lung cancer cells from the cerebrospinal fluid using daily high-dose gefitinib for 2 weeks, followed by 2 weeks of maintenance gefitinib,” he reported. Novel means of overcoming resistance are in development, including three irreversible EGFR inhibitors: PF299804, BIBW2992, and HKI-272. Other potential approaches are to combine a TKI with cetuximab (Erbitux), a strategy that reduced tumor burden in a study presented at the 2010 ASCO Annual Meeting.7 TKIs might also be combined with inhibitors of PI3 ki-

Table 1: Mutations in 541 Lung Adenocarcinomas Assessed in LC-MAP Number

Percent of Specimens (95% CI)

KRAS

143

26% (23%–30%)

EGFR*

119

22% (19%–26%)

Mutation

EML4-ALK

8% (4%–16%)

PIK3CA

0.7% (0.1%–2%)

MEK1

0.4% (0%–1%)

BRAF

0.2% (0%–1%)

HER2

0% (0%–0.8%)

AKT1

0% (0%–0.8%)

* Primarily exon 10 deletion (n = 55) and exon 21 mutation (n = 49). LC-MAP = Lung Cancer Molecular Analysis Project. Courtesy of Mark Kris, MD.

nase, mTOR, heat shock protein 90, or c-MET. Amplification of c-MET is a key mechanism of resistance, and recent phase II data suggested dual inhibition with erlotinib and the c-MET inhibitor ARQ197 might be effective.8 Meanwhile, clinicians should remember that EGFR mutations also predict for response to chemotherapy, “so standard chemotherapy is of value in the second-line setting,” Dr. Jackman said. “The larger question is whether to keep the patient on the TKI,” he added. “In patients with indolent disease, sometimes continuing the TKI alone can provide long-term benefit. When you remove the TKI, tumors threaten to flare. My bias is to keep the TKI and give chemotherapy on top of this, rather than make a wholesale switch.”

Sloan-Kettering Genotyping All Lung Adenocarcinomas Clearly, the key to optimally treating NSCLC is to unravel the genetic makeup of the patient’s tumor. The Lung Cancer Molecular Analysis Project at Memorial Sloan-Kettering Cancer Center (MSKCC) is seeking to do just that by routinely testing all NSCLC specimens for mutations in EGFR and KRAS, which are the most common, along with 40 additional abnormalities in seven genes. EGFR mutations are found in approximately 19% to 26% of adenocarcinomas, making them highly sensitive to EGFR inhibitors. About 23% to 30% of tumors have KRAS mutations, which appear to be associated with treatment resistance. MSKCC oncologists use the test results to select patients for treatment

with erlotinib or gefitinib and to identify patients’ eligibility for biomarkerdriven clinical trials, said Mark Kris, MD, Chief of the Thoracic Oncology Service at MSKCC, at a poster presentation at the Annual Meeting.9 Table 1 shows the frequency of various mutations revealed in data on 541 tumors assessed by the lung cancer molecular analysis project (Table 1). “The [lung cancer-molecular analysis] program has permitted molecular testing in 96% of patients with available tissue. We detected a driver mutation in 6%, and the program guided the selection of therapy in 18% of patients with EGFR, KRAS, and EML4-ALK mutations. The [lung cancer-molecular analysis project] findings support making upfront genotyping of lung adenocarcinomas part of routine care,” Dr. Kris said. Protocols for agents targeting BRAF, MEK1, HER2, and PIK3CA are in the approval process, and the investigators will collaborate with Lung Cancer Mutation Consortium institutions to complete trials of agents targeting these mutations.

Elsewhere, Oncologists Slow to Order Molecular Tests While NSCLC patients at MSKCC are tested for an array of molecular alterations, the average American oncologist takes the opposite approach. According to a survey conducted by Xcenda, LLC, a full-service consultancy, market research, and managed markets agency in the healthcare space, 62% of American medical oncologists would not order molecular testing before treating a hycontinued on page 26

The ASCO Post | SEPTEMBER 2010

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Special Feature

Targeting EGFR in Lung Cancer

studies on the tissue before finalizing their management plans, and were presented with 10 testing options. Prior to treating, 60% of oncologists would order no molecular tests, including 64% of those in community practice and 51% in academic settings (Fig. 1). For those who would test, the single most common choice was for EGFR status, which was selected by just 10% of respondents; 9% would order at least two of the following: EGFR, KRAS, or ERCC-1. No clear correlation was seen between time out of training or volume of lung cancer patients and plans for more frequent testing. “The notion here, among nearly 600 medical oncologists, is ‘I am not persuaded by the discussion, the data, and the analyses [in support of testing] that the clinical impact is enough to consider these tests mandatory for optimum treatment,’” Dr. Green told The ASCO Post. While he proposed a number of reasons for their reluctance, he said, “The bottom line is that from March through September 2009, the majority of oncologists, who had substantial lung cancer experience, were not planning to use molecular studies as a basis

continued from page 25

pothetical stage IV NSCLC patient.10 “Only a minority of consultants planned to order specific testing to assess possible chemosensitivity (ERCC-1) or KRAS or EGFR status,” said Mark R. Green, MD, Chief Medical OffiSee page 43 cer of Xcenda, Palm Harbor, Florida, at another poster presentation at the Annual Meeting. He and his colleagues queried 585 oncologists as to how they incorporate marker testing in their treatment planning for a hypothetical 58-yearold female, former smoker presenting with stage IV lung adenocarcinoma. Three-quarters of respondents were in community practice and one-quarter practiced in academic centers or teaching hospitals. About half had practiced for at least 11 years and saw at least one new NSCLC patient per week. Participants were asked whether they would request special marker 70% 60% 50%

64%

Yes, KRAS mutation status Yes, EGFR by IHC

40%

Yes, all 3 studies

20%

References 1. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009. 2. Fukuoka M, Wu Y, Thongprasert S, et al: Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia. 2010 ASCO Annual Meeting. Abstract 8006. Presented May 31, 2010. 3. Rosell R, Moran T, Queralt C, et al:

Yes, at least 2 of the 3 studies (ERCC-1, KRAS, EGFR)

30%

10%

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Yes, ERCC-1

51%

11%

Academic or Teaching Institution (n = 57)

10%

Community Practice (n = 191)

Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958-967, 2009. 4. Mitsudomi T, Morita S, Yatabe Y, et al: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomized phase 3 trial. Lancet Oncol 11:121-128, 2010. 5. Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR. N Engl J Med 362:2380-2388, 2010. 6. Paz-Ares L, Soulières D, Melezinek I, et al: Clinical outcomes in non-small-cell lung cancer patients with EGFR mutations: Pooled analysis. J Cell Mol Med 14:51-69, 2010. 7. Riely GJ, Janjigian YY, Azzoli CG, et al: Phase II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. 2010 ASCO Annual Meeting. Abstract 7557. Presented June 6, 2010. 8. Schiller JH, Akerley WL, Brugger W, et al: Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer. 2010 ASCO Annual Meeting. Abstract LBA7502. Presented June 5, 2010. 9. Kris MG, Lau CY, Ang D, et al: Initial results of LC-MAP: An institutional program to routinely profile tumor specimens for the presence of mutations in targetable pathways in all patients with lung adenocarcinoma. 2010 ASCO Annual Meeting. Abstract 7009. Presented June 8, 2010. 10. Green MR, Wozniak AJ, Willey J, et al: Plans of American medical oncologists to order molecular testing before starting first-line therapy for patients with stage IV non-small cell lung cancer. 2010 ASCO Annual Meeting. Abstract 7568. Presented June 6, 2010. 11. Gazdar AF: Personalized medicine and inhibition of EGFR signaling in lung cancer. N Engl J Med 361:1018-1020, 2009.

for finalizing their management plans.” It should be noted that most respondents were surveyed prior to the publication of two high-profile studies1,3 and a relevant editorial in The New England Journal of Medicine.11 Dr. Green acknowledged that if surveyed today, some oncologists might answer differently. Indeed, over time there was an increase in the proportion of physicians who would order at least one test, from 28% initially to 46% by mid-September 2009. Commenting on the findings, Dr. Kris suggested, “There is a widely held but unsubstantiated belief that erlotinib is helpful, regardless of mutation status. Many physicians are giving erlotinib, especially secondline, without testing. But the data are incontrovertible that any benefit is trivial in unselected patients. Plus, the maintenance benefit of chemotherapy is twice that of erlotinib, and from the [Pan-Asia] study we know that a TKI may actually be detrimental in wildtype patients. You need to test these patients, and as time goes on I think more doctors will realize this.” Xcenda is continuing to survey oncologists on this and related issues in order to create “a matrix of information” that will guide the personalization of NSCLC care, Dr. Green said.

Yes, EGFR copy number by FISH Yes, EGFR mutation testing Yes, KRAS and EGFR by IHC and EGFR by FISH or mutation testing Yes, other

Fig. 1: Survey results according to practice venue, for a subset of all medical oncology consultants surveyed, from 3 of 8 live research events (results were similar for the remainder of the total population). Respondents were asked whether they would order any of several marker studies for a hypothetical 58-year-old female, former smoker presenting with stage IV lung adenocarcinoma. EGFR = epidermal growth factor receptor; FISH = fluorescence in situ hybridization; IHC = immunohistochemistry. Courtesy of Mark R. Green, MD.

The ASCO Post’s TAP Caucus June 2010: Should oncologists participate in physician-assisted suicide? July 2010: Should oncologists own imaging services? View the debates by visiting ASCOPost.com. We encourage you to share your opinions on these and other important issues in oncology. Send your thoughts to Editor-in-Chief, Dr. James Armitage, at Editor@ASCOPost.com. Your letters will be published in future issues of The ASCO Post. See page 41 for this issue’s debate, “Is accelerated partial-breast irradiation acceptable care in patients receiving breast-conserving treatment?”

AS CO Po

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d Physician-assiste

Suicide g

sician-aided Dyin Support of Phy

acker, MD By Nancy Crump

“physiuse the phrase hy do I no longer ”? It is simply inaccian-assisted suicide d to distinguish the emerge curate. The phrase asia, which suggests lack of practice from euthan the patient. But “physicianof choice on the part its own connotation prob” has assisted suicide ian-aided lems. Washington, physic In Oregon and al Death with ed by nearly identic dying is regulat specifically to A) that pertain (DWD Acts y Dignit peaceful death. t in achiev ing a cker, MD , because Nancy Crumpa physician suppor suicide a in g regulate assistin DWDA does not es In both states, the medical practic that is still a crime. e” to describe similar medical treatment the word “suicid aw or withhold We do not use pres to choose to withdrpractice allows physicians to patient g allowin l like food medica sciousness while death. Current that will cause patient into uncon the sedates that ing death. scribe medication withheld, thus hasten and hydration is

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| JUNE 2010 ASCO Post.c om

icia Imagin Offer H n-owned Imag g Servic ig es? Services h-quality, In ing Centers tegrated By Rober Physicia t M. Lan gdon, MD Imagin ns Should Not g Own Ce By Charle nters s L. Ben nett, MD T he ability of an ,

d Suicide Is Physician-assiste ective, and Ineff Unnecessary, gerous Increasingly Dan By Kevin Olson,

d medications I have prescribe nts A for a few patie under the DWD are ect those who because I resp ing ibly experienc dying and poss to able be I may not suffering that ameliorate. istic Distinction word “suicide” demeans people The More Than a Lingu ent deaths. Peonot just linguistic.

is immin The distinction manner of their tes: in the timing and suicide are opposi to who wish a choice and those who would commit but does not wish ple using the DWDA is generally physically healthy to live. person is dying but wishes ■ The suicidal who uses the DWDA ones. DWDA deaths live. The person tragedy to loved . s bring shock and friends suicide l and family ■ Typica allows are supported by under our law bring closure and and violent. Dying often impulsive ■ Suicides are are em. DWDA deaths r a peaceful death.

| JU LY 2010

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suicide physician-assisted or reliy opposition to oncology PhD, MP operate from purely ethical practic P, and E.W (PAS) stems less tic concerns with hig its own imagin . Lingle, more from pragma perspecg center e to own and her qua PhD lity, pro gious ideology and and con care. My sistent care better efficien vides patients y of this kind of about the deliver ters pro cy, ing hematology/ . Physici vid full-time practic an-owned lower costs, as the and tive comes as a years work wit e improved qua imagin an for the past 16 lity thro h oncolo hysicians e oncologists oncology physici ugh coll g cengic to practic read rad private 40 iolo abo of ing not ow should leader of a group ge has had many can ensure scans from a can gists who are ded rative n the The PAS challen 10. ow imRob icat cer past ng qua n the ert M. Lan ed ir view for includi lity imaging nization gdon, MD uences in Oregon end of life, centers. s such as through accred . These centers Period. beneficial conseq the itation wit the End of The pra palliative care at ies and ma cticing onc American Co h orgaThe Un story. proved focus on n ranks among lleg utilization (Orego als, these ke special reques with on-site rad ologist can imm e of Radiology. spends mo ited States Kevin Olson, MD improved hospice se in the maniologists ts rad re of its ed training and experti the end of to review ediately consult characteris iologists are attu in regard to issu improv , on GDP regard) near hea this Char es in the patient lth by those les L. Benn the nation’s leaders a reduced fear of painful death and other tics to meet Res ned to providing under question. ett, MD, ’s studother cou care than any PhD, MPP However, three main Du and pon PAS. acc crit via pain, ring ntr of se t ura eria death d Evaluation y, and clin te agemen e, and large and set in patient share is who pursue a hastene not always effectiv Criteria tumor measurem ical triincreasing migration forth in the tria rising. Sup that E.W. Ling life—even for those tion to PAS: It is not needed, it is in Sol nent of l. The ents le, PhD ers of from ima maze of y system. hea our hea portging cen affiliated facility id Tumors (RE and x medical care deliver issues drive my opposi tween $58 lth-care costs— regulatory req CIST) ter to ima provides an increasingly comple uirements system point lth-care ging cen The effi it is dangerous in annually billion and $34 and unnecessar to the as an imp ter for pro for reduction ciency y 0 is cedures. When ship of out derived from phy billion annually. costs at that—acc ortant compoof an on within This e it is rarely used. Another patient faci ounting sicians’ a multidi cology Not Needed s with cancer becaus “100-10-2-1” rule. That tori esti add patient for befor es, litie ma itio imaging day-surger sciplina te s, nal PAS is not needed s for PAS, I use the of be- center is y facilitie including diagno income that resuis that $8 billion ry frees extraor (often in the panic frequency of request s, and pro stic lts tanding center asked about the ask about the option pursue the legal process dinary. Conflict cedure labo imaging centers from ownerindividuals who to cancer of Intere , testing is, for every 100 with allo ratories. sis), only 10 begin tely diagno comple al h laboraConflict-o st a termin ws only 2 follow throug ing informed of inter- stag easy access f-interest and Overuse Empirical ption. Of those 10, for the dying process ing and concer of Fac of obtaining a prescri a prescription (often because ptions,wh tumor respthe imaging pro powerfu studies in medic ns affect the ent ilities obtain two who get prescri en there l. the process and d death). For the are questio onse on therap cedure to consist tories, imaThey consistent ine concerning ire economy, not need for a hastene y. It also ently asse ns of rela ly con venes without the pro ss accura pse, pro excess in ging equipment show that when flict of interest just health care Full-spe use it. gression, vides a rapid te . one will actually the use , pha ctrum phy are

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ASCOPost.com | SEPTEMBER 2010

PAGE 27

FDA Update

Oncology Drug News FDA Grants Priority Review to Denosumab The FDA has granted priority review designation to Amgen’s denosumab (Prolia), a subcutaneous RANK ligand inhibitor, for the treatment of bone metastases to reduce skeletal-related events in patients with cancer. Filed in mid-May with the FDA, the Biologics License Application (BLA) submission summarizes clinical experience from nearly 6,900 patients across 18 clinical studies, including approximately 5,700 patients with advanced cancer in the three pivotal phase III head-to-head trials vs zoledronic acid (Zometa). Denosumab is the first therapy to target the RANK/RANKL pathway, which is believed to play a central role in cancerinduced bone destruction.

guidance on its bone marrow transplant program following a formal meeting with the FDA. For this phase III program, patented allogeneic adult mesenchymal precursor cells (MPCs) will be used under an Orphan Drug designation

to expand unrelated donor hematopoietic stem and progenitor cell numbers for use in patients with hematologic malignancies. In the meeting with the FDA, Mesoblast proposed a phase III clinical trial whose design, size, duration,

and primary endpoints were based on results from the 25-patient pilot trial performed at The University of Texas M. D. Anderson Cancer Center. Mesoblast will seek to obtain a binding Special Protocol Assessment prior to commencing the trial.

New Docetaxel Formulation Approved The FDA has approved a new one-vial formulation of sanofi-aventis’s docetaxel (Taxotere Injection Concentrate). The 1-vial docetaxel is anticipated to become available to cancer treatment clinics and hospitals nationwide in the fall in both 80and 20-mg dosages. Previously, docetaxel was available in a two-vial formulation— one containing the drug and the other with the diluent. The 1-vial docetaxel eliminates the need for the initial dilution step with the diluent. The pharmaceutical ingredients of docetaxel and the 1-hour IV infusion administration remain the same.

Perifosine Receives Orphan Drug Designation in Neuroblastoma

We are here, where you need us most We are committed to the discovery and development of innovative immunotherapeutic approaches aimed at helping patients fight cancers, such as advanced melanoma. Together, we can make a difference.

Perifosine (licensed by Keryx from Aeterna Zentaris in the United States) has received Orphan Drug designation from the FDA for the treatment of neuroblastoma, a cancer of the nervous system affecting mostly children and infants for which there are no FDA-approved therapies. Phase I data of perifosine in recurrent pediatric solid tumors, including neuroblastoma, was presented at the 2010 ASCO Annual Meeting. Investigators concluded that perifosine was safe and well tolerated in children with advanced solid tumors and that perifosine may have antitumor clinical activity as a single agent in neuroblastoma.

Phase III Bone Marrow Transplant Trial on Track after FDA Meeting An Australian biotechnology company, Mesoblast Ltd, provided market ©2010 Bristol-Myers Squibb. All rights reserved. 731US10AB00705 4/10

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The ASCO Post | SEPTEMBER 2010

PAGE 28

Expert’s Corner Reimbursement

A Conversation with Joseph S. Bailes, MD, ASCO Immediate Past Chair of Government Relations Medicare Drug Reimbursement Roundup By Caroline Helwick

t the 2010 ASCO Annual Meeting’s Reimbursement Forum, Joseph S. Bailes, MD, of Texas Oncology, Austin, described the 2010 changes to Medicare reimbursements and made some predictions regarding future reimbursement issues.

Prompt Pay Discounts What is happening with regard to “prompt pay” discounts? Dr. Bailes: Prompt pay discounts confound average sales price (ASP) calculations. ASCO is advocating the amendment of the Medicare ASP calculation to exclude them (H.R. 1392/S. 1221), which would increase the ASP and the Medicare payment. Congress has already excluded prompt pay discounts from the average manufacturer price (AMP), which is used to calculate Medicaid payment rates. The House included a provision to exclude prompt pay discounts under Medicare within H.R. 3200, a near-final version of the health-care reform bill, but the provision did not survive in the final legislation.

Biosimilars As biologics go off-patent and generics come on board, what will be the reimbursement policy for the so-called biosimilars? Dr. Bailes: Health-care reform leg-

islation created a new pathway for biosimilars. Medicare reimbursement for these products reflects a compromise, differing from the payment methodology used for traditional generics. The original reference biologic will be paid at ASP plus 6% based on its own sales data—nothing changes. The biosimilar product will be paid the sum of 100% of ASP from its own sales data plus 6% ASP from the reference product’s sales data.

Chemotherapy Administration How has reimbursement for chemotherapy administration been affected? Dr. Bailes: For 2010, the Centers for Medicare and Medicaid Services (CMS) implemented cuts in payment levels for chemotherapy administration codes. CMS used new data for determining practice expenses and relied on a survey administered by the American Medical Association, the Physician Practice Information Survey (PPIS). However, the survey had significant flaws, and we secured some relief when CMS agreed to instead use the Gallup survey for oncology. Despite this, the adverse impact of the PPIS data from other specialties resulted in net decreases for chemotherapy administration within the fixed pool.

‘We Need to Permanently Fix SGR’

ll other reimbursement issues pale in comparison to the lack of a permanent fix for the sustainable growth rate (SGR). With each go-round on the subject, “Congress just kicks the can down the road,” said Joseph S. Bailes, MD, ASCO’s Immediate Past Chair of Government Relations. “Congressional interventions over the years have merely delayed the impact of the SGR mechanism rather than reset the base. As a reJoseph S. Bailes, MD sult, the cuts from prior years have continued to accumulate,” he said, noting that the cost of enacting a permanent fix is now reaching $250 billion. “We all have SGR fatigue, and so does Capitol Hill.” On June 24, the House of Representatives voted once again—this time, 417 to 1—to delay the 21.3% reduction in Medicare pay for physicians through November 30, but by December 1 the mandated SGR cut is expected to occur. ASCO continues to advocate for a permanent legislative fix that removes the accumulation of delayed cuts from the mechanism and puts an end to the “month-to-month patches” long endured by oncologists.

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CMS has agreed to phase in changes over a 4-year period (2010-2013). For 2010, this results in an overall estimated 1% cut for oncology.

Medical Malpractice Is there any relief to be found within the medical malpractice relative value units (RVUs)? Dr. Bailes: CMS proposed the reduction of malpractice RVUs assigned to codes with zero physician work values to near zero levels. This approach failed to recognize the malpractice risk associated with chemotherapy administration codes. CMS agreed to modify the proposed changes to reflect the associated amount of clinical labor. This mitigated the reductions, although some decline occurred in these codes, particularly in the malpractice risk part.

Consultation Codes What are the changes in consultation codes? Dr. Bailes: There has been continuing debate as to when and how to use these codes. CMS eliminated payment under Medicare fee-for-service for consultation codes (except for telehealth consultation codes), effective January 1, 2010. This follows a history of unclear guidance from CMS and the Office of the Inspector General on when to use the consultation codes vs codes for new patient visits or hospital admissions. CMS redistributed the RVUs for consultation codes in a budget-neutral manner to the codes for new and established patient visits. The consultation codes still exist, and other payers (including Medicare Advantage) may still use them, but that does not mitigate their elimination from Medicare.

Competitive Acquisition Program Is the Competitive Acquisition Program (CAP) for Medicare Part B drugs dead? Dr. Bailes: Congress is still interested in CAP, so we need to keep an eye on this. The intention of CAP is to remove financial pressures associated with the profit or loss of providing a drug therapy. Congress originally envisioned competing vendors that would serve physician offices and compete

on the basis of quality. Vendors would negotiate pricing with manufacturers, and vendor bids to CMS would be less than ASP plus 6% for each drug. CMS struggled to get CAP up and running, but only a single vendor was secured and CAP was suspended, although it remains a dormant authority that CMS can restart at any time.

Outpatient Prospective Payment System What changes were made for drug reimbursement through the Outpatient Prospective Payment System (OPPS)? Dr. Bailes: The OPPS allows for more expensive drugs to be paid for separately, whereas payment for less expensive drugs is bundled. CMS has a great deal of discretion in implementing changes in the drug payment formula in the hospital outpatient setting. For 2010, the package threshold is $65 and the methodology for establishing drug payment levels remains at ASP plus 4%, which was set in 2009. One significant change was in reimbursement for 5-HT3 receptor antagonist antiemetics. These drugs were originally paid separately, regardless of the threshold. For 2010, however, CMS reversed this determination, and Medicare no longer pays separately for any oral or injectable 5-HT3 receptor antagonist except for palonosetron (Aloxi), which exceeds the $65 threshold.

Radiopharmaceuticals How are therapeutic radiopharmaceuticals paid? Dr. Bailes: For 2010, these were moved to ASP plus 6% reimbursement. Separate payment for these products was maintained, and the expense of making the product into a “patient ready” form is covered. Diagnostic radiopharmaceuticals remain packaged within payment for services.

Off-label Use What’s new in coverage of off-label use of cancer drugs? Dr. Bailes: The list of compendia and peer-reviewed journals as a basis for determining coverage was recently updated, largely a result of ASCO’s efforts. This is good news, but in some instances Medicare contractors are

ASCOPost.com | SEPTEMBER 2010

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Expert’s Corner

imposing burdensome documentation requirements to provide information from all four compendia to support claims. Difficulties remain in securing access to off-label uses not reflected in the compendia, especially under Medicare Part D.

Other Coverage What’s the future of coverage for endof-life care and patient education? Dr. Bailes: There were provisions included in the House version of the health-care reform bill that would have helped cover decision aids for individuals with cancer as they decided on treatment. This coverage (advanced cancer care consultation) pertains to consultations about advance directives, continuum of end-of-life services

(including palliative care and hospice), and related issues. These end-of-life provisions were excluded from the final version of the bill because of the highly politicized rhetoric that became associated with the issue. It is important, however, to have decision aids for patients as they look at therapy, and these decision aids are certainly a ben-

efit that should be covered. The issue is likely to resurface in the future. Regarding hospice, there is a budget neutrality provision—that is, payment may be limited to current hospice payment levels, the current language suggests. Demonstration projects currently underway should inform the issue of hospice reimbursement. Regarding

patient education, ASCO is supporting a proposal by the Oncology Nursing Society to establish separate Medicare coverage for nursing time spent on education about cancer treatment and symptom management. The legislation would also expand federal research in this area and establish a study by the Institute of Medicine.

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Information You Can Trust and Your Patients Can Understand

For discussions with patients about their cancer care and treatment, you want to be sure that the information you provide is not just the best available, but also easy to understand. That’s why ASCO offers a variety of oncologist-approved educational materials for doctors to share with their patients.

Contact The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief email: Editor@ASCOPost.com Cara H. Glynn, Director of Editorial email: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash, Assoc. Director of Editorial email: Andrew@harborsidepress.com Phone: 631.935.7657

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Whether you need a comprehensive guide to a specific kind of cancer or just a list of available resources, ASCO can help:

ASCO Patient Education Each cancer education resource uses illustrations to aid comprehension and is updated annually or as needed by a 150-member editorial board of practicing oncologists, nurses, social workers, and patient advocates. ASCO Answers Fact Sheets A double-sided page introducing a cancer type.

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Doctor-approved cancer information in one comprehensive website. Cancer.Net is your resource for the most trusted and up-to-date cancer information, developed by the world’s leading cancer doctors. Cancer.Net brings the expertise and resources of the American Society of Clinical Oncology (ASCO), the voice of the world’s cancer physicians, to people living with cancer and those who care for and care about them.

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Cancer Information Prescription:

For information about ASCO’s patient information resources, call toll-free 888-651-3038.

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Cancer.Net is your resource for the most trusted and up-to-date cancer information, developed by the world’s leading cancer doctors.

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Order your patient education materials at www.cancer.net/ordermaterials or by calling 888-273-3508.

The ASCO Post | SEPTEMBER 2010

PAGE 30

News Health Economics

‘Financial Survival’ a Challenge to Oncologists By Caroline Helwick

ommunity oncologists are devising ways to stay afloat as they brace for the “perfect economic storm” making landfall on their practices. At a 2010 ASCO Annual Meeting session called “The Challenge of Financial Survival,” speakers described their view of these uncharted waters.

Elaine L. Towle, CMPE

Indeed, many practices are feeling the pinch of a difficult economy and are being forced to evolve, said Elaine L. Towle, CMPE, Director of Oncology Services at Oncology Metrics, a division of Altos Solutions, Los Altos, California. This is clear from the National Practice Benchmark, an annual survey of some 200 U.S. practices that her company conducts. “Total collected revenue in these practices increased 6% from 2007 to 2008, and at first glance this is good news. However, total practice expense increased 16% over the same period, resulting in fewer dollars available to support practice operations,” she said. “When practice expenses rise more rapidly than revenue, the result is lower physician incomes.” The most recent survey (2009) revealed a shifting practice landscape. Some 73% of respondents were still independent physician-owned practices but many were consolidating: 11% were practicing oncology within a multispecialty group, 6% were hospital-owned

physicians or hospital employees, 5% were physician-owned but had a hospital or corporate affiliation, 2% were affiliated with US Oncology, 1% were academic-affiliated and 2% reported “other” practice settings. Perhaps more telling were their predictions: only 15% envisioned their practices/business structure remaining “unchanged and viable” for at least 5 years, while 19% said they are “changing now” and 53% predicted they will be stable only for “the foreseeable future.”

ore and more oncologists are leaving practice to join hospital-based cancer centers and clinics, “seeking refuge from the seemingly endless buffetings of 7 years of health-care ‘reform,’” said Jeffrey C. Ward, MD, an oncologist/hematologist with Puget Sound Cancer Centers, Edmonds, Washington, who participated in the ASCO session, “The Challenge of Financial Survival.” “Oncologists who have made this transition report no disruption to patient care, only minor limitations to physician autonomy, decreased stress, and a relatively high level of satisfaction with their current practice circumstances,” noted Dr. Ward, drawing from surveys by the Washington State Medical Oncology Society and his personal observations.

Eye of the Storm

What Are the Hospital-based Options?

Oncologists considering a new business model are mainly concerned about declining physician compensation, the survey suggested. This was cited as a reason for change by 54% of the survey respondents, while others cited loss of referrals due to competition (19%) and the need to reduce practice overhead (15%). Interestingly, only 4% said reduced reimbursements were a reason for change and just 3% listed lower drug cost margins. But oncologists have seen drug margin as a percentage of total revenue increasingly fall, from 45% in 2002 to just 9% today, according to Ms. Towle, who said this contributes to the “dramatic decline” in the funds available to run one’s practice. Revenue related to drugs is more important than ever, she maintained (see Fig. 1), adding, “If drug management is not a core competency in your practice, you are losing revenue. The ‘new normal’ is low-margin, high-volume.”

The professional services agreement is the simplest. Under this model there are fully integrated clinical services, but the physicians and/or practice remain an independent contractor. Several structures are possible: (1) the hospital contracts with the practice for global payment, and the practice provides management; (2) the hospital employs physicians, but the practice remains physician-owned and contracts with the hospital; (3) the hospital owns the practice and contracts with physicians for professional services; or (4) the hospital employs or contracts with physicians, and the practice is spun off into a joint venture. Professional service agreements make sense for a number of reasons, Dr. Ward maintained. Practice and hospital incentives are aligned, physicians retain a measure of independence and control, some measure of exclusivity is allowed, and the structure is relatively simple. But, he added, hospitals may pay only the “fair market value of the practice,” Stark laws and anti-kickback statutes may come into play, and independent contractors must provide their own benefits and malpractice coverage. Under this model, 340B drug pricing may or may not be allowed, which can be an advantage or disadvantage depending on one’s perspective, he added. The advantages of full employment, on the other hand, are independence from drug revenue and the “stigma” of drug revenue, financial stability, shared malpractice risk, freer lifestyle, infrastructure support, full benefits, and other things lacking under a professional services agreement system. “But you lose independence and flexibility, it requires a common vision, there is no guarantee of long-term financial success, it is difficult to reverse, and it takes lots of time and effort to make it happen,” Dr. Ward pointed out. Regardless of one’s preference, he concluded, partnering with a hospital in some fashion or another “may prove to be the only reality available to people in practice” and offers hidden opportunities. “Hospitals need physician partners, not just employees,” he explained, “and whether they know it or not, hospitals desperately need physician leadership. If oncologists who have run a practice leave that skill set behind when they join a hospital, both the oncologist and the hospital will miss opportunities.”

More Problems and Pressures The “perfect storm” is also fueled by greater regulatory exposure, information overload, scarcity of resources, increased practice size, and an emerging patient profile in which more and more Medicare patients lack secondary Radiation 7%

Drugs 69%

Drug Management must be a core competency in your practice

Infusion 8% Imaging 3% Lab 2% Evaluation and management 8%

Nonmedical 3% Fig. 1: Revenue mix in a typical oncology practice. Revenue related to drugs is more important than ever. Adapted with permission from Elaine L. Towle, CMPE.

Hospitals as Partners: Oasis or Refuge?

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insurance. As a result, oncologists are increasing their referral of patients for chemotherapy visits outside of their offices. In the survey, 33% of oncologists referred up to 400 visits in 2009, and 9% referred more than 1,000. More drain on resources comes from the handling of insurance and payer issues, with the average practice employing 1.2 billing staff for every physician and 0.4 patient financial advocates.

Time to Start Adapting “Pay-for-service is going away; new systems will pay for quality and

outcomes,” Ms. Towle emphasized. Many practices have started adapting, and good first steps are to become involved in a demonstration project, initiate clinical process measurements, and perhaps partner with others to increase efficiency. Partnering is especially beneficial in areas that require capital or specialized, highly paid staff for procedures such as radiotherapy, imaging, and infusion therapy. The main point, she concluded, is, “The good ol’ days are gone. New practice models are developing. Investigate and embrace them.”

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Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

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Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a significant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2004. Data on file, GTx, Inc.

Please see full prescribing information on the following page. For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro1,2-diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

COOH

CH2COOH

and the molecular formula is C26H28CINO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch. CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growthstimulating effects of estrogen in the tumor. Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h. Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin. Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied. Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed. CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table). Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 14+33 11+30 7+25 3+28 19+48 19+56 CR1 + PR2 RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.) 5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.) 33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median

survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

Race: Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% 2% Vomiting 4% Vaginal Bleeding 2% 4%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug. WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis). Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/ kg/day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly. There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended. Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum. Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides. This interaction has not been studied and its clinical relevance is uncertain. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice. Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses. Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks. Pregnancy: Pregnancy Category D: (see WARNINGS). Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS). Pediatric use: There is no indication for use of FARESTON in pediatric patients. Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below. Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal). Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. FARESTON Tablets are identified with TO 60 embossed on one side. FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from heat and light.

ASCOPost.com | SEPTEMBER 2010

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TAP on Technology

Multiparameter Gene Profile Assays for Predicting Recurrence of Colon Cancer By Matthew Stenger his year saw the introduction of the first commercially available multiparameter gene profile assay for predicting risk of recurrence of colon cancer after surgery. The Oncotype DX colon cancer assay (Genomic Health) for predicting risk of recurrence in patients with stage II disease was launched in January 2010, and the ColoPrint assay (Agendia) is likely to be available soon. Methods for better quantifying risk of recurrence after surgery in patients with stage II disease are needed, because patients at higher risk of recurrence may experience a relatively greater benefit from adjuvant chemotherapy. Such treatment is associated with only a small absolute survival benefit in this setting, while posing a risk of toxicity in all who receive it.

761 candidate genes in samples from 1,851 patients in four colon cancer treatment studies. The seven genes used in the assay were selected from among 76 showing statistical associations with recurrence in these studies.

Whole Genome oligonucleotide microarrays. Multivariate analysis identified a 38-gene signature associated with risk of development of distant metastases. The signature was validated in an independent group of 178 stage II or

therapy is in combination with established clinicopathologic factors.

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Additional Resources on Oncotype DX Kerr D, Gray R, Quirke P, et al: A quantitative multigene RT-PCR assay for predic-

Oncotype DX Like the Oncotype DX breast cancer assay, the Oncotype DX colon cancer assay uses real-time reverse transcription polymerase chain reaction (RT-PCR) technology to measure levels of select cancer-related genes compared with reference genes. RNA is extracted from manually microdissected formalin-fixed, paraffin-embedded tumor tissue, and DNase I treatment is used to eliminate DNA contamination (Fig. 1). RT-PCR is performed to quantify expression of seven cancerrelated genes, and expression is normalized to expression of a set of five reference genes, providing the basis for calculating a recurrence score (0– 100). The seven cancer-related genes (Ki-67, C-MYC, MYBL2, FAP, BGN, INHBA, GADD45B) include cell-cycle and stromal genes that were consistently associated with a recurrencefree interval in development studies. The availability of high-throughput RT-PCR made it possible to evaluate

Fig. 1: Technology underlying gene profile assays to predict colon cancer recurrence. RNA is extracted from tumor tissue, and DNA microassays are used to determine levels of expression of cancer-related genes.

In a validation study involving 1,436 patients with stage II disease, the continuous recurrence score was significantly and nearly linearly associated with recurrence risk (P = .004). The 3-year recurrence risk ranged from 9% to 11% at low recurrence score (< 30, 44% of patients) to 25% to 27% at high recurrence score (≥ 41, 26% of patients). On multivariate analysis, recurrence score, T stage, and mismatch repair (MMR) status were the most important independent predictors of recurrence.

ColoPrint

See page 43

For more information on gene profiling in colorectal cancer, use your smartphone to follow the links in the above barcode.

Like the Agendia MammaPrint breast cancer assay, the ColoPrint assay uses DNA microarray technology to determine levels of expression of cancer-related genes in fresh frozen tumor samples. In development studies, gene expression in frozen tumor tissue from 188 colon cancer patients with stage I to III disease was measured on Agilent 44K

III samples and in in-silico data sets (n = 322). In the validation study, patients identified by the ColoPrint signature as high-risk (39% of patients) had a significantly greater risk of distant metastases (HR = 3.2, P = 8.5e-4) compared with low-risk patients (61% of patients). The 5-year distant metastasis-free survival rate was 89% for low-risk patients and 62% for high-risk patients. Prediction of recurrence with the ColoPrint signature was significant in both stage II disease (P = .0058) and stage III disease (P = .036). Multivariate analysis showed the signature to be the most prognostic factor. To make the test suitable for clinical use, the profile was translated into a diagnostic test using an Agilent 8-pack format that supports high throughput. These assays help to refine risk of recurrence in early-stage colon cancer. For the present, their optimal use in selecting patients for adjuvant chemo-

tion of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study 2009 ASCO Annual Meeting. Abstract 4000. Abstract presented May 31, 2009. Glas AM, Roepman P, Salazar R, et al: Development and validation of a robust prognostic and predictive signature for colorectal cancer (CRC) patients. 2009 ASCO Annual Meeting. Abstract 4036. Abstract presented May 30, 2009. Additional Resources on ColoPrint Salazar R, Marshall J, Stork-Sloots L, et al: The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint. 2010 ASCO Annual Meeting. Abstract TPS199. Poster presented June 7, 2010. Rosenberg R, Maak M, Nitsche U, et al: Independent validation of a prognostic genomic profile (ColoPrint) for stage II colon cancer (CC) patients. 2010 ASCO Annual Meeting. Abstract 3513. Poster presented June 8, 2010.

The ASCO Post | SEPTEMBER 2010

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Appointments

UCCC Names New Director

Fred Hutchinson Cancer Research Center Announces New President and Director, Lawrence Corey

continued from page 17

Dr. Theodorescu trained as a urologic oncologist at Memorial-Sloan Kettering Cancer Center in New York. He received his PhD degree in molecular and cell biology from the University of Toronto under the mentorship of internationally known cancer biologist Dr. Robert Kerbel.

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Dan Theodorescu, MD, PhD

Lawrence Corey, MD

The Fred Hutchinson Cancer Research Center board of trustees has an-

Higher Impact, 17.793 Higher Value Over 100K Citations Journal of Clinical Oncology (JCO) has strengthened its position as publisher of the most important clinical oncology research, with higher scores recorded in all key measures of a journal’s impact on the scientific community. As reported by Thomson Reuters in its just-released 2009 Journal Citation Reports®: •

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TAP Caucus Is accelerated partial-breast irradiation acceptable care in patients receiving breastconserving treatment?

The Eigenfactor Project is a non-commercial academic research project sponsored by the Bergstrom lab in the Department of Biology at the University of Washington. The Eigenfactor method considers the past five years’ Thomson Reuters journal-to-journal citation network, excluding self-citations, so that highly cited journals affect the score more than lesser cited journals.

See page 41 in this issue and share your thoughts by writing to Editor@ASCOPost.com.

To Submit a manuscript, contact JCO Editorial PHONE: (703) 797-1900 | E-MAIL: jco@asco.org | ONLINE: www.submit.jco.org ASC_101186 JCO Impact Factor Ad 2_V8.indd 1

nounced the selection of Lawrence Corey, MD, an internationally renowned expert in virology, immunology, and vaccine development, as its new President and Director. Dr. Corey is expected to begin responsibilities as the Center’s new leader on January 1, 2011. Dr. Corey is known internationally for his research in infectious diseaserelated cancers, HIV infection, and medical complications of patients with compromised immune systems. “It will be a great privilege to work with our faculty, staff, and board members to extend and expand the Center’s excellence,” said Dr. Corey, whose academic medical career spans more than 3 decades. He is perhaps best known for his expertise in leading complex scientific coalitions and partnerships in the United States and abroad, including an international clinical trials network dedicated to HIV-vaccine development. Dr. Corey’s research focuses on novel therapies and vaccines for human viral infections, in particular herpesviruses, HIV, and infections related to cancer. He is also particularly interested in expanding the Center’s research in understanding the role cancer plays in global health. Dr. Corey also is principal investigator of the Hutchinson Center– based HIV Vaccine Trials Network, an international collaboration of scientists and institutions that combines clinical trials and laboratory-based research to accelerate the development of HIV vaccines. In addition to his research, Dr. Corey is an infectious disease physician at the Seattle Cancer Care Alliance. Dr. Corey earned his bachelor’s and medical degrees from the University of Michigan. He received his infectious diseases training at the University of Washington School of Medicine, where he joined the faculty in 1978. He moved his laboratory to the Hutchinson Center in 1997.

8/3/10 4:28:26 PM

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News Breast Cancer

For Bevacizumab, Third-party Payers Look to NCCN By Caroline Helwick

he FDA’s Oncologic Drugs Advisory Committee (ODAC) concluded that bevacizumab (Avastin) conveys little benefit in advanced breast cancer, but the occasional patient has prolonged remission with little toxicity. This is the patient subset that may stand to lose the most, should the FDA withdraw the label for bevacizumab. Lori Baur, a patient with triple-negative breast cancer from Sleepy Hollow, New York, belongs to this group. She told The ASCO Post, “I’m just 41 years old and I have an aggressive cancer, including brain lesions that have disappeared but will probably rebound if I go off [bevacizumab]. I am pleading with the FDA not to take this drug away from patients like me who are responding to it.” But interviews with several private insurers offer some reassurance to patients like Ms. Baur, and the oncologists who treat them. Lee Newcomer, MD, Senior Vice President, Oncology, at UnitedHealthcare, told this newspaper that he agrees with ODAC’s recommendation, but his company will not stop covering bevacizumab for current responders. “We think ODAC’s opinion was important. We never felt bevacizumab should have been approved originally because the data show no increase in overall survival (OS), and now there is the emergence of toxicity. The drug is an important step scientifically, but it is not ready for the clinic in breast cancer,” he said in an interview.

Coverage Decisions Dr. Newcomer’s personal opinion aside, UnitedHealthcare bases cover-

age decisions on the recommendations of the National Comprehensive Cancer Network (NCCN), he pointed out. “This takes the decision-making to the academic experts who we feel are best qualified to make the call, and secondly, the process is transparent,” he said. “So for us, the NCCN would also need to withdraw its recommendation, which I am sure it will consider if the FDA sides with the panel. If the NCCN still believes we should cover bevacizumab, we will.”

Lee Newcomer, MD

erage. Meanwhile, any patient insured by UnitedHealthcare who has been started on bevacizumab, regardless of future policy changes, will be allowed to continue until disease progression, he emphasized. Aetna’s position is similar. “If breast cancer is removed by the FDA as an indication for bevacizumab, Aetna would consider removing coverage, but we would also consider the position of the NCCN on this issue, as we have cov-

James Cross, MD

UnitedHealthcare is currently developing a new review process for bevacizumab using NCCN recommendations. “We are no longer just matching the drug with the diagnosis. We are looking at three other specific things that NCCN recommends: which drug it is paired with, what line of therapy, and when to discontinue it [upon progression],” he said. In 2009, UnitedHealthcare provided coverage for bevacizumab to 55% of patients not meeting all the NCCN recommendations. The company will now enforce all three recommendations as a requirement for cov-

Harold Burstein, MD, PhD

ered drugs for indications in NCCN’s Compendium with a consensus rating of 2b or greater,” said James Cross, MD, Head of National Medical Policy and Operations. Aetna will make provisions to allow continued coverage, however, for persons already completing a course of therapy, he added. Otherwise, the drug would not be covered. “Participating physicians who wish to prescribe bevacizumab for breast cancer would have to inform patients in writing that this would not be covered by their health plan, and they would be afforded the opportunity to appeal any adverse de-

Coming in the October 2010 issue of ■■ News from the 2010 UICC World Cancer Congress, Shenzhen, China ■■ News from Best of ASCO ■■ TAP Caucus: Do Patients with Limited-stage Hodgkin Lymphoma Require Radiotherapy? ■■ Plus, Direct from ASCO, Important Perspectives, Oncology Drug News, and more

Be sure to visit The ASCO Post online at ASCOPost.com.

termination. We would continue to cover bevacizumab for breast cancer where mandated by applicable legal requirements of a state, or CMS requirements for Medicare and Medicaid members,” he told The ASCO Post.

NCCN Guideline Process The importance of the NCCN Breast Cancer Panel, therefore, becomes clear. Panel member Harold Burstein, MD, PhD, of Dana-Farber Cancer Institute, Boston, said that should the FDA withdraw the indication, as part of its regular review the NCCN panel would reconsider the appropriateness of keeping bevacizumab plus paclitaxel as an acceptable regimen. “The NCCN has a sophisticated guideline process, and there will be opportunities to review any FDA decision. We meet annually to review recent data and hear new opinions. And we often meet ad hoc when the FDA approves a new drug, though I can’t say we have ever met because the FDA withdrew a drug,” Dr. Burstein said. He noted that FDA approval does not dictate the NCCN’s recommendations. “There are breast cancer drugs on our list of recommended treatments for advanced breast cancer that are not FDA-approved for this indication. For example, we list as single agents doxorubicin, epirubicin, pegylated liposomal doxorubicin (Doxil), vinorelbine, and cisplatin, which are not FDAapproved, and gemcitabine, which is approved only in combination. We also list paclitaxel/carboplatin/trastuzumab (Herceptin) and trastuzumab/ capecitabine, which are not FDA-approved regimens.”

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In the News Breast Cancer

Answering Questions Your Patients May Ask about the Role of Bevacizumab in Metastatic Breast Cancer By Charlotte Bath In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

hen the FDA issued an accelerated approval for the use of bevacizumab (Avastin) for metastatic breast cancer, the approval was contingent on additional clinical trials demonstrating efficacy for that indication. Now, nearly 2½ years later, the results of those trials have prompted FDA’s Oncologic Drugs Advisory Committee (ODAC) to recommend that the FDA withdraw its approval of bevacizumab for metastatic breast cancer. The recommendation was widely reported by national news organizations, including the business press, which specuSee page 43 lated on the potential economic impact if bevacizumab loses its FDA-approved indication for metastatic breast cancer, and the medical media, which looked at what it might mean to patients and physicians if the FDA decides to accept ODAC’s recommendations.

Patients Want Answers “I’m getting questions from patients who are on bevacizumab about what this will mean for them,” said Nicholas Robert, MD. “Will they be able to con-

tinue to stay on the drug? That, of course, may depend on what FDA says, but it is hard if you have someone that has metastatic breast cancer and is doing well on a bevacizumab regimen to stop that regimen.” Dr. Robert is Associate Chair of the Breast Committee of US Oncology, a physician practice management group with about 1,200 oncologists, Chair of the Cancer Committee at INOVA Fairfax Hospital in Virginia, and an ASCO University faculty member. He also served as principal investigator of RIBBON-1, one of the two new studies ODAC analyzed before making its recommendations. “For patients who are tolerating treatment and responding, it would probably be prudent for the FDA to permit them to stay on treatment until they experience disease progression or develop a complication,” Dr. Robert said. “It would be pretty tough from a patient perspective to stop a regimen if you are doing well on it.” In the US Oncology practice, that would primarily involve patients using first-line paclitaxel and bevacizumab, the combination used in the E2100 study that led to FDA’s accelerated approval in 2008 of bevacizumab for advanced breast cancer. “I was the principal investigator for the RIBBON-1 study and serve as a consultant and lecturer for Roche, so I am familiar with both research and clinical considerations. From a clinical perspective, I do think weekly paclitaxel with bevacizumab should still be available, and I think that opinion is shared by a lot of people in the breast cancer community,” Dr. Robert said. He added that the combination of capecitabine (Xeloda) and bevacizumab, which was

Expect Questions

he widespread reporting of the recommendation to withdraw FDA approval of bevacizumab for the treatment of metastatic breast cancer is sure to raise questions among concerned patients. Some of the answers will depend on the FDA’s decision, but here’s what we know now. What did ODAC recommend? The Oncologic Drugs Advisory Committee of the FDA recommended that bevacizumab no longer be approved for women with metastatic breast cancer. The committee voted unanimously that two new studies that were required for bevacizumab to complete the approval process (following an accelerated approval in 2008) do not “provide confirmatory evidence of clinical benefit of bevacizumab in combination with paclitaxel for the initial treatment of [metastatic breast cancers].” The committee voted 12 to 1 that “the indication for treatment of metastatic breast cancer be removed from the Avastin label.” When will the FDA make its decision? The FDA is expected to decide later in the year whether or not to accept ODAC’s recommendation. If FDA decides to go along with ODAC, will bevacizumab still be available to patients with advanced breast cancer? Yes. Physicians would still be able to use bevacizumab off label to treat patients with metastatic breast cancer. The use of bevacizumab off-label rather than for an FDA-approved indication, however, might affect costs and insurance coverage for bevacizumab, which could in turn limit its accessibility for patients (see page 35 for more on insurance implications). Does the FDA’s decision affect other indications for the use of bevacizumab? No. The FDA’s decision on the use of bevacizumab for metastatic breast cancer will not affect the drug’s FDA-approved indications for metastatic colorectal cancer, metastatic nonsquamous non–small cell lung cancer, and metastatic renal cell carcinoma.

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used in one arm of the RIBBON-1 study, should also be an option for women with metastatic breast cancer.

Is Progression-free Survival a Meaningful Endpoint? Dr. Robert attended the ODAC

The Challenge of Overall Survival

ost trials in metastatic breast cancer do not use overall survival as the primary endpoint, according to Dr. Robert. “It’s a very uncommon endpoint,” he said. “It is always nice to see [an improvement in overall survival] achieved, but I don’t think it should be the sole metric or a necessary metric if you see a significant progression-free survival with acceptable toxicity.” Using overall survival as an endpoint “is a very big challenge for a number of reasons,” Nicholas Robert, MD he noted. While a crossover

design “is a bit of a carrot to encourage people to participate in a clinical trial,” it also means “you are reducing the chance of showing an impact on overall survival, because there may be some benefit in second-line treatment.” That was actually demonstrated in RIBBON-2, where everybody gets first-line chemotherapy, and then is randomly assigned to chemotherapy or chemotherapy plus bevacizumab. Thus, some patients are getting bevacizumab in the second-line setting, where there was a progressionfree survival of about 2 months. Another reason overall survival is challenging as an endpoint is because breast cancer is quite heterogeneous, Dr. Robert said. Although median survival is 2 to 3 years, many patients are living even longer.

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meeting as an observer. “It was an interesting process,” he remarked, “because there seemed to be a few things going on that are frankly unresolved. One is the debate about progressionfree survival vs overall survival. A number of us in the breast cancer community who do research feel that progression-free survival is potentially a clinically meaningful endpoint.” Dr. Robert noted that progression-free survival was the primary endpoint for the three trials the FDA used in making its decision on bevacizumab for advanced breast cancer—the E2100 trial that prompted the accelerated approval and the follow-up RIBBON-1 and AVADO trials. In all three trials, the drug combinations used were active and “succeeded achieving the endpoint of each trial, which was progression-free survival statistically, and that was never a debate,” Dr. Robert said. “No one argued that the progression-free survival data were not robust. The issue

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In the News

was the trade-off with side effects, and the problem I had was that all of the trials were put into one category.” He argued that “another approach” would have been to look at the data for the different drug regimens and approve the combination regimens that produced clinically meaningful results, which he considers to be paclitaxel with bevacizumab, as used in the E2100 trial, and capecitabine plus bevacizumab, as used in one arm of the RIBBON-1 trial.

tial strategy. Registry data show that “women are living longer with stage IV breast cancer today than 20 years ago, and that is partly due to having multiple treatments available so you can use that strategy,” he added. All of the women in the cited studies were HER2-negative and therefore not candidates for hormonal therapy.

“So you only have chemotherapy,” Dr. Robert pointed out. Paclitaxel and capecitabine without bevacizumab also “are very reasonable regimens,” he said. “If bevacizumab is not available, we will continue to use the arsenal of agents we have available and continue to use single agents. We have other drugs.”

For more perspectives on the role of bevacizumab in advanced breast cancer, see pages 2, 10, and 11.

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What about Toxicity? “The other big issue” discussed by ODAC, Dr. Robert noted, “was the concern about toxicity, which is real.” Hypertension is not uncommon as a side effect of bevacizumab, he said, “but we are all internists—oncologists in this country are specialists in internal medicine first. We can manage hypertension. We can manage neutropenia and febrile neutropenia. Those are complications of treatment, and it’s our job to manage the complications. I’ve not had a patient for whom I’ve had to hold bevacizumab for hypertension, because we monitor patients for that and we treat it,” he said. “All of the drugs we use for chemotherapy have risks for toxicity, and it is really an art in terms of how to use them carefully so you don’t produce harm. It is the art of managing patients with metastatic breast cancer, the art of oncology.” Dr. Robert argued that the toxicity “is acceptable given the gains” of an additional 5.5 months of progression-free survival in the E2100 study, and an additional 2.9 months of progression-free survival in the capecitabine arm of the RIBBON-1 study. “For me that would have passed muster as a risk-benefit ratio that was acceptable, worthy of use, and worthy of being available in clinical practice,” he said.

(Stimulating Targeted Antigenic Responses To NSCLC)

What Is the Chronic Disease Model? “The more drugs we have available, the more treatments we have available for the patient, the better chance we have of keeping the patient’s disease under control for a longer period of time,” Dr. Robert said. “The rationale is that we think of metastatic breast cancer as a chronic disease, and we give sequential treatment, moving from one drug to another drug.” According to this rationale, “if a drug produces a few more months of controlled cancer,” it could be useful as part of the sequen-

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

The ASCO Post | SEPTEMBER 2010

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In the Literature

Emerging Clinical Data on Cancer Diagnosis and Management BREAST CANCER Triple-negative Breast Cancer More Common in African and African-American Women Women of African ancestry are more likely to have breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER2/neu, according to a study published online in the journal Cancer. The primary study population included 581 African-American women and 1,008 white women diagnosed with breast cancer at the Henry Ford Health System in Detroit, and a comparison group of 75 African women diagnosed at the Komfo Anokye Teaching Hospital in Ghana. Of these patients, 82% of the African women were triple-negative, compared to 26% of the African-Americans, and 16% of the white Americans. Researchers also found that the Ghanaian women were diagnosed at a younger age than American women, and with larger tumors and more advanced cancer. In addition, the Ghanaian women were more likely to test negative for each of the three markers.

Increasing Outcome Disparities “The most significant recent advances in breast cancer treatment have involved targeting these three receptors. But these treatments do not help women with triple-negative breast cancer. Outcome disparities are therefore likely to increase, because fewer African-American women are candidates for these newer treatments,” remarked Lisa A. Newman, MD, MPH, one of the study authors. Dr. Newman is Director of the Breast Care Center at the University of Michigan Comprehensive Cancer Center, and Professor of Surgery at the University’s medical school. “Our study documented provocative patterns of increasing frequency for early onset/younger age at diagnosis, ER-negative/PR-negative, and triple-negative breast cancers in association with presumed increasing extent of African ancestry. These patterns suggest that further study of the breast cancer burden in African women could lead to the identification of tumor or germline markers associated with high-risk breast cancer,” the investigators wrote. “Hopefully, these markers will ultimately have potential utility for targeted therapy of the triple-negative

phenotype, for which we are currently limited to chemotherapy as systemic treatment.” Stark A, et al: Cancer July 13, 2010 (epub ahead of print)

Genetic Risk Scores for Breast Cancer Are Highly Predictive of ER-positive Disease An analysis of breast cancer risk, overall and by tumor subtype, in relation to 14 individual single-nucleotide polymorphisms (SNPs) and to a polygenic risk score found that the polygenic risk score was highly predictive of estrogen receptor–positive disease. Investigators from the United Kingdom and France estimated the per-allele odds ratio for individual SNPs and the cumulative incidence of breast cancer to age 70 years in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most strongly associated with risk. The study included 10,306 women with breast cancer (average age at diagnosis, 58 years) and 10,393 women without breast cancer, who in 2005–2008 provided blood samples for genotyping. The odds ratios for breast cancer were greatest for the SNPs FGFR2rs2981582 and TNRC9-rs3803662 and, for these two SNPs, were significantly greater for ER-positive than for ER-negative disease—both in the data from this study and in metaanalyses of other published data. The next strongest association was for 2qrs13387042, for which the per-allele odds ratio was significantly greater for bilateral than unilateral disease and for lobular than ductal tumors.

Subdivision by Risk “When the effects of the seven SNPs most strongly associated with overall breast cancer risk in these data were combined using a polygenic risk score, the cumulative risk of breast cancer to age 70 years among women in the top fifth was twice that in the bottom fifth (8.8% vs 4.4%). Both the relative and, particularly, the absolute difference was much greater for ER-positive disease (7.4% vs 3.4%) than for ER-negative disease (1.4% vs 1.0%),” the authors wrote. “Certain established risk factors for breast cancer have similar, or even greater, effects on breast cancer incidence than the differences seen here between women in the highest vs the lowest fifth of polygenic risk score. Indeed, our estimate of the cumula-

tive incidence of breast cancer to age 70 years in women in the top fifth for polygenic risk score (8.8%) is similar to that for women in developed countries with one first-degree relative with breast cancer (9.1%), and considerably less than that for women with two affected first-degree relatives (15.4%),” the researchers concluded. “Furthermore, no interactions have been found between the effects of the genes investigated here and the other risk factors for breast cancer. Hence, as others have suggested, subdividing women on the basis of their polygenic risk is, at this stage, not a useful tool for population-based breast cancer screening programs but may be useful for understanding disease mechanisms.” Reeves GK, et al: JAMA 304:426-434, 2010.

PROSTATE CANCER Sipuleucel-T Prolongs Survival in Men with Castrate-resistant Metastatic Prostate Cancer Men with metastatic castrationresistant prostate cancer who received sipuleucel-T (Provenge) had a 22% relative reduction the risk of death (P = .03), representing a 4.1-month improvement in median survival, compared with the placebo group in a multicenter phase III trial reported in The New England Journal of Medicine. The authors concluded that among men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer, sipuleucel-T prolonged overall survival, the primary endpoint of the trial. No effect from sipuleucel-T was observed for the secondary endpoint of time to objective disease progression. Sipuleucel-T is an active cellular immunotherapy that has shown survival benefit in previous trials. For this double-blind study, known as the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study, 512 patients were randomly assigned in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. All patients had previously received androgen-deprivation therapy. Median survival was 25.8 months in the sipuleucel-T group vs 21.7 months in the placebo group. The 36-month survival probability was 31.7% in the sipuleucel-T group vs 23.0% in the placebo group.

Consistent Results Across Subgroups “In our study, the effect of sipuleucel-T on survival was observed consistently across subgroups of patients, including those with prognostic factors known to be adversely correlated with overall survival, such as increased levels of PSA, lactate dehydrogenase, and alkaline phosphatase, as well as an increased number of bone metastases, an increased Gleason score, a decreased performance status, and the presence of pain,” the authors wrote. The treatment effect of sipuleucel-T was also observed after adjusting for use of docetaxel, which most patients in both groups received following use of the study therapy. The authors stated that sipuleucel-T was well tolerated. In an editorial in the same issue of The New England Journal of Medicine, Dan L. Longo, MD, noted that the results of the clinical trial reported by Kantoff el al, “helped convince the FDA to approve sipuleucel-T for clinical use.” He added that other immunization strategies being tested for patients with prostate cancer include the vaccines GVAX and PROSTVAC-VF and the experimental drug MDV3100. “The prospects for improved therapy for prostate cancer have never been so encouraging,” he commented. Kantoff PW, et al: N Engl J Med 363:411422, 2010. Longo DL: N Engl J Med 363:479-483, 2010.

LYMPHOMA Relapsed/Refractory NHL Study Shows High Rates of Responses with Anti-CD22 Fractionated Radiotherapy An objective response (OR) rate of 62% was achieved among patients with relapsed/refractory non-Hodkgin lymphoma (NHL) who received two or three weekly infusions of yttrium-90 (90Y)-epratuzumab tetraxetan (humanized anti-CD22 antibody) in a phase I/II trial. Median progressionfree survival (PFS) was 9.5 months. The multicenter trial involved patients at several European centers as well as the Garden State Cancer Center in Belleville, New Jersey, and included 17 patients who had prior autologous stem cell transplantation (ASCT). Within the overall OR rate of 62% for 61 evaluable patients, 48% of patients

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In the Literature

achieved a complete response (CR) or complete response unconfirmed (CRu). Patients without prior ASCT had higher OR rates—71%, with a CR/Cru rate of 55% —across all NHL subtypes and 90Y doses. This was true even in poor-risk categories. For example, patients with disease refractory to their last anti-CD20–containing regimen had a 73% OR rate and a 60% CR/CRu rate, and those with bulky disease had a 71% OR rate and a 43% CR/Cru rate. Patients who had previously had ASCT received lower doses of radioimmunotherapy and achieved an OR rate of 41% (CR/CRu, 29%). For patients with follicular lymphoma (FL), OR rates and median PFS increased with total 90Y dose, reaching 100% OR (CR/CRu, 92%) and 24.6 months PFS at the highest dose levels (> 30 mCi/m2 total 90Y dose [1,110 MBq/ m2]). Patients with FL refractory to prior anti-CD20–containing regimens achieved 90% OR and CR/CRu rates and a median PFS of 21.5 months. Most treatment-related adverse effects were mild to moderate (grade 1 or 2). The exceptions were two cases of severe neutropenia, one with febrile neutropenia. The high rates of durable CR/CRus achieved with high total doses of 90Y fractionated anti-CD22 radioimmunotherapy in patients with relapsed/ refractory NHL resulted in recommendations that 20 mCi/m2 × 2 weeks be used as the dose in future studies. The authors also noted that 90Y-epratuzumab tetraxetan could also be used as part of a combination approach for relapsed/refractory NHL. Morschhauser F, et al: J Clin Oncol 28:3709-3716, 2010.

SURVIVORSHIP Two Studies Mine Long-term Data on Health Risks among Childhood Cancer Survivors Two studies—one reported in the Journal of the American Medical Association (JAMA) and the other in the Journal of the National Cancer Institute (JNCI)—confirm that survivors of childhood cancer are at increased risk of subsequent cancers and provide more details on the long-range impact of childhood cancer and its treatment. The JAMA study found that childhood cancer survivors had excess mortality from second primary cancer and circulatory disease beyond 25 years from di-

agnosis. The JNCI study concluded that survivors of Hodgkin lymphoma are at greatest risk of developing another neoplasm. Other factors associated with increased risk in the JNCI study were being female, older age at time of diagnosis, receiving therapy in an earlier treatment era, and receiving radiation therapy.

Expanded Analysis The JNCI study represents an expanded analysis of the Childhood Cancer Survivor Study. For the analysis, the incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14,359 people treated from 1970 through 1986. Their median age was 30 years, with a range of 5 to 56. Among these survivors, 1,402 subsequently developed 2,703 neoplasms. The calculated cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% for all subsequent neoplasms, 7.9% for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% for nonmelanoma skin cancer, and 3.1% for meningioma. “Excess risk was evident for all primary diagnoses,” the authors reported, “with the highest being for Hodgkin lymphoma and Ewing sarcoma.” For the cohort of patients treated for cancer between 1970 and 1986, “it is clear that continued surveillance for subsequent neoplasms is essential, as their risk continues to increase as these survivors enter their third and subsequent decades of life,” the authors concluded. “The continued surveillance is of particular importance because many adult survivors do not appreciate the health risks that are related to their childhood cancer and so do not have regular medical follow-up or practice recommended screening.”

ratio declined with follow-up, but was still three times higher than expected 45 years from diagnosis. The absolute excess risk for deaths from recurrence declined from 97 extra deaths per 10,000 person-years at 5 to 14 years from diagnosis, to 8 extra deaths beyond 45 years from diagnosis. During the same periods of follow-up, the absolute excess risk for deaths from second primary cancers increased from 8 extra deaths to 58 extra deaths, and the absolute excess risk from circulatory causes (which includes cardiac and cerebrovascular deaths) increased from 2 extra deaths to 29 extra deaths. Beyond 45 years from diagnosis, recurrence accounted for 7% of the excess number of deaths observed, whereas second primary cancers and circulatory deaths together accounted for 77%. “These findings confirm the importance of very long-term outcome data and that survivors should be able to access health-care programs even decades after treatment,” the investigators commented. “The excess morality due to second primary cancers and circulatory diseases is likely attributable to late complications of treatment,” they added. They acknowledged, however, that a potential limitation of the study is the lack of detailed data on radiotherapy and chemotherapy exposures. In addition, they noted, survivors in the study were treated between 1940 and 1991, and “findings may not be translatable to survivors treated in more recent years.” Friedman DL, et al: J Natl Cancer Inst 102:1083-1096, 2010.

Reulen RC, et al: JAMA 304:172-179, 2010.

GUIDELINES Guideline Summaries Offer Quick Synopses for Clinicians Two Guideline Summaries published in the July issue of the Journal of Oncology Practice provide outlines of clinical recommendations recently issued by ASCO. Condensing key patient management recommendations to a few pages, JOP Guideline Summaries are intended to assist busy oncology practitioners in clinical decision-making. A summary by Elizabeth Hammond, MD, and coauthors offers an overview and discussion of recommendations for immunohistochemical (IHC) testing of estrogen and progesterone receptors in patients with breast cancer. Jointly developed by ASCO and the College of American Pathologists, these guidelines are aimed at improving the accuracy of IHC. In the same spirit, Timothy Gilligan, MD, and colleagues present a summary of ASCO’s clinical practice guideline on the use of serum tumor markers in men with germ cell tumors. The authors address screening, diagnosis, monitoring during treatment, and post-therapy surveillance of patients with seminoma and nonseminomatous germ cell tumors. Hammond MEH, et al: J Oncol Pract 6:195-197, 2010. Gilligan TD, et al: J Oncol Pract 6:199202, 2010.

■

Largest Study of Its Kind The JAMA study used data from the British Childhood Cancer Survivor Study, a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer before age 15 years between 1940 and 1991 in Britain and followed up until the end of 2006. The authors noted that it “is the largest population-based cohort study to comprehensively examine the late effects of childhood cancer and its treatment.” Overall, 3,049 deaths were observed, which was 11 times the number expected based on cause-specific standardized mortality ratios. That

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ASCOPost.com | SEPTEMBER 2010

PAGE 41

TAP Caucus Pro/Con

Is Accelerated Partial-breast Irradiation Acceptable Care in Patients Receiving Breast-conserving Treatment? By Simon Powell, MD, PhD, and Lawrence J. Solin, MD, FACR, FASTRO

PRO

One of the major recent changes in radiotherapy for early-stage breast cancer is the selective use of accelerated partialbreast irradiation (APBI). The attraction of APBI is the accelerated delivery of treatment, which in most cases condenses the traditional 6-week course of treatment into just 1 week. A shorter treatment time is feasible because the target of therapy is limited to the affected quadrant rather Simon Powell, MD, PhD than the entire breast. The rationale for the use of APBI is that 85% to 90% of recurrences after wide local excision alone occur in the same quadrant of the breast as the initial cancer.1 In this classic study, the use of radiation therapy resulted in a significant reduction in breast cancer deaths, although

The rationale for the use of APBI is that 85% to 90% of recurrences after wide local excision alone occur in the same quadrant of the breast as the initial cancer.

CON

For the patient with early-stage breast cancer, the gold standard for radiation treatment after breast-conservation surgery remains whole-breast radiation (often with a boost), not accelerated partial-breast irradiation (APBI). Breast-conservation treatment with whole-breast radiation has been studied in many randomized clinical trials conducted worldwide, with data from tens of thousands of treated paLawrence J. Solin, MD, tients.1 These clinical trials have demonstrated FACR, FASTRO equivalent survival for breast-conservation treatment with radiation compared to mastectomy with 20 years or more of followup. Adding whole-breast radiation after breast-conservation surgery (lumpectomy) improves the rate of local control in the treated breast, and leads to an improvement in breast cancer mortality and overall survival. In addition to primary endpoints of local control and survival, a great deal is known about secondary endpoints after breast-conservation treatment, such as detection and treatment of local recurrence, optimization of cosmetic outcome, minimization of complications, and timing and integration of radiation with surgery and systemic therapy.

Limitations of Supporting Arguments not in overall survival. This discrepancy potentially suggests that the use of radiation therapy carries with it some long-term survival risks, which have been reported for postmastectomy radiation. Meta-analysis of the use of radiation therapy in conjunction with conservative surgery also shows a survival benefit.2 The conclusion is that radiation therapy can reduce breast cancer recurrence and improve breast cancer survival, but can the same be achieved with less radiation and potentially fewer long-term complications?

Which Breast Cancer Patients Are Appropriate for APBI? Not even the most ardent supporter of APBI feels that all patients receiving conservative breast surgery are suitable for APBI. The current U.S.-based randomized trial of APBI vs conventional whole-breast irradiation allows enrollment of patients with tumors up to 3 cm in size and up to three positive axillary lymph nodes.3 However, many institutionally based studies use more stringent entry criteria, such as only T1N0 patients.4 Based on recruitment to the randomized trial, less than 5% of the patients have positive nodes, so there is a degree of selection being carried out by the accruing physicians. I would argue that the presence of lymphatic invasion or positive lymph nodes puts the whole breast and adjacent chest wall (including the skin) potentially at risk. Given that many would consider administering postmastectomy radiotherapy in this setting, APBI would logically be less appropriate. The opponents of adopting APBI may focus on the difficulty in selecting the appropriate patient, but the factors influencing local control or multifocal disease within the breast are well defined. When present, these factors make the patient less suitable for APBI. Another potential criticism of APBI is that case selection makes the need for radiotherapy debatable. However, in a study of wide local excision without radiotherapy for good-risk T1N0 breast cancer, the projected recurrence rate was over 20% at 5 years.5 The results of the initial studies of APBI have been reported with actuarial follow-up of 9.5 years,6 and the local control rate is over 95%, equivalent to matched pairs of patients treated with conventional whole-breast irradiation.

APBI is a change in the paradigm for delivering radiation treatment after lumpectomy for patients with early-stage breast cancer. Arguments typically cited to support the use of ABPI are that nonrandomized phase I/II trials substitute for randomized phase III trials, and that other new technologies have been implement-

Rather than using theory to debate whether APBI is clinically valid, the focus should be on accruing patients to ongoing randomized clinical trials. ed without randomized clinical trials. These arguments are of course scientifically invalid, and randomized clinical trials remain the gold standard for evidence-based medicine. Consensus statements and expert opinion cannot substitute for scientific evidence. A number of ongoing randomized clinical trials in Europe, Canada, and the United States are comparing standard whole-breast radiation treatment to APBI. In the United States, an open randomized clinical trial is being conducted jointly by the National Surgical Adjuvant Breast and Bowel Project and the Radiation Therapy Oncology Group (NSABP B‑39/RTOG-0413). Another argument commonly cited to support APBI is patient convenience, given the reduced overall treatment time. There are now accelerated whole-breast radiation treatment regimens that substantially shorten overall treatment time, but with supporting scientific evidence from randomized clinical trials that report up to 12-year outcomes.2-4 One commonly used accelerated whole-breast radiation treatment regimen uses 16 fractions, not much greater than the 10 fractions used in many APBI regimens.

Other Practical Concerns

The use of APBI is associated with more detailed three-dimensional mapping of the target volume than has been traditional in breast cancer radio-

Published reports of APBI have shown large variations for patient selection, radiation dose fractionation, and techniques for radiation delivery. Far too little is known about the long-term consequences of APBI, including detection of local recurrence, salvage treatment for local recurrence, mammogram findings, and late complications. Late complications are a particular concern when, as in APBI, large radiation fractions are used.5 In two older randomized trials of APBI, the rate of local recurrence was higher for APBI in comparison to

continued on page 42

continued on page 43

Accurate Planning and Delivery Becomes an Important Factor in Breast Radiotherapy

The ASCO Post | SEPTEMBER 2010

PAGE 42

TAP Caucus

Partial-breast Irradiation Is an Acceptable Option continued from page 41

therapy. One of the reasons for the success of APBI may be better target delineation by planning and, although not required for the randomized trial, the use of image-guided radiotherapy (IGRT) for more precise delivery of

NEW

treatment if external beams are used.7 The optimum dose, delivery schedule, and target volume for APBI are yet to be finalized, although 32 to 40 Gy given over 4 to 5 days in not more than 4 Gy per fraction is the current practice in the United States. The target volume receiving the prescribed dose can vary widely by the applied technique.

As a physician who supports the use of APBI in selected patients with early-stage breast cancer, I would advocate that further research is needed to define the optimum method for delivering APBI. Patients should continue to accrue to appropriate clinical trials so that we can continue to perfect this alternative method of radiother-

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apy, which patients find so appealing in its brevity and lack of side effects. In 2010, there is sufficient evidence to support that APBI is acceptable care in conjunction with conservative surgery for selected patients with early-stage breast cancer.8 References 1. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002. 2. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005. 3. NSABP B-39, RTOG 0413: A randomized phase III study of conventional whole breast irradiation versus partial breast irradiation for women with stage 0, I, or II breast cancer. Clin Adv Hematol Oncol 4:719-721, 2006. 4. Lawenda BD, Taghian AG, Kachnic LA, et al: Dose-volume analysis of radiotherapy for T1N0 invasive breast cancer treated by local excision and partial breast irradiation by low-dose-rate interstitial implant. Int J Radiat Oncol Biol Phys 56:671680, 2003. 5. Schnitt SJ, Hayman J, Gelman R, et al: A prospective study of conservative surgery alone in the treatment of selected patients with stage I breast cancer. Cancer 77:1094-1100, 1996. 6. Vicini FA, Kestin L, Chen P, et al: Limited-field radiation therapy in the management of early-stage breast cancer. J Natl Cancer Inst 95:1205-1210, 2003. 7. Bert C, Metheany KG, Doppke KP, et al: Clinical experience with a 3D surface patient setup system for alignment of partial-breast irradiation patients. Int J Radiat Oncol Biol Phys 64:1265-1274, 2006. 8. Smith BD, Arthur DW, Buchholz TA, et al: Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 74:987-1001, 2009. Dr. Powell is Chair of the Department of Radiation Oncology at Memorial Sloan-Kettering Cancer Center, New York.

Tell Us What You Think Write to Editor@ASCOPost.com and share your viewpoint on APBI. Selected responses will be published in a future issue.

ASCOPost.com | SEPTEMBER 2010

PAGE 43

TAP Caucus

Partial-breast Irradiation Is Not an Acceptable Standard of Care continued from page 41

whole-breast radiation treatment.6,7 Two more recent trials of APBI showed no difference in local recurrence, although they reported local recurrence at only 5 years and 4 years, respectively, and acknowledged the need for longer follow-up.8,9 Rather than using theory to debate whether APBI is clinically valid, the focus should be on accruing patients to ongoing randomized clinical trials. Such trials would provide evidence-based outcomes with which physicians and patients could make informed decisions about local treatment options. Unfortunately, some physicians have promoted the rapid introduction of this new tech-

nology into clinical practice without adequate scientific evidence, even though randomized clinical trials can be properly conducted and reported. Physicians would best serve patients by supporting randomized trials of APBI. References 1. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005. 2. Whelan TJ, Pignol J-P, Levine MN, et al: Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 362:513-520, 2010. 3. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al: The UK Stan-

dardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 9:331-341, 2008. 4. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al: The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet 371:1098-1107, 2008. 5. Bentzen SM, Yarnold JR. Reports of unexpected late side effects of accelerated partial breast irradiation—radiobiological considerations. Int J Radiat Oncol Biol Phys 77:969-973, 2010. 6. Dodwell DJ, Dyker K, Brown J, et al: A randomised study of whole-breast vs. tumour-bed irradiation after local excision and axillary dissection for early breast cancer. Clin Oncol (R Coll Radiol) 17:618-622, 2005.

7. Ribeiro GG, Magee B, Swindell R, et al: The Christie Hospital breast conservation trial: An update at 8 years from inception. Clin Oncol (R Coll Radiol) 5:278-283, 1993. 8. Polgar C, Fodor J, Major, T et al: Breast-conserving treatment with partial or whole breast irradiation for low-risk invasive breast carcinoma—5-year results of a randomized trial. Int J Radiat Oncol Biol Phys 69:694-702, 2007. 9. Vaidya JS, Joseph DJ, Tobias JS, et al: Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): An international, prospective, randomised, non-inferiority phase 3 trial. Lancet 376:91-102, 2010. Dr. Solin is Chairman of the Department of Radiation Oncology, Albert Einstein Medical Center, Philadelphia.

What Are Two-Dimensional Barcodes? two-dimensional (2D) barcode, also known as a matrix code, is a graphic image that contains information stored both horizontally (like the one-dimensional UPC used in supermarkets) and vertically. The added dimension in a 2D barcode enables the image to represent thousands of characters—essentially a portable database—compared with only 10 to 20 characters stored in the conventional unidimensional barcode. Given that added capacity, 2D barcodes are increasingly being used for fast data access in a variety of settings, and in documents from drivers’ licenses to tax returns. Perhaps not surprisingly, the real boom in 2D barcode use has been in mobile marketing. Companies have developed technology that enables camera phones to scan matrix codes from a website, print publication, or poster. The consumer can then access content embedded in the code or be redirected to targeted content via the phone’s Web browser. The 2D barcodes used in this issue of The ASCO Post will connect readers to further information about the articles they are reading. For instance, a report from the ASCO Annual Meeting may include a barcode that will connect readers online to the original abstract of the study discussed. In this way, the editors of The ASCO Post hope to provide readers with further resources and validated information about the news in these pages. Find examples of 2D barcodes on the pages of this issue. Using the ScanLife application (see right), scan these codes with your camera phone, and see where they bring you. Watch for more barcodes in future issues of The ASCO Post.

Important: Getting the application There are 3 ways to download the ScanLife application. 1. Simply text the word “scan” to 43588. Or 2. Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”. Or 3. Visit the application store for your smartphone (such as the iTunes Store or the Android Market). The application is free, though standard data rates for your phone do apply.

Scanning 2D codes When you see a code that you would like to scan, start the ScanLife application. The screen will look similar to camera mode. Position your phone so that you can see the barcode and that the code fills about half of your screen. If one of the soft keys displays the word “Click,” you will need to click that key or the center key to scan. Otherwise, the code will scan automatically. A short audio chime will indicate a successful scan and the phone will contact the server for further instructions. This may take up to a minute depending on data speeds and phone type.

What’s this?

www.BioOncology.com

After multiple lines of HER2+ MBC treatment

What’s next?

Options can run out for patients with HER2+ metastatic breast cancer When faced with how to treat advanced HER2+ metastatic breast cancer, the answer is never simple. While there is a wide variety of agents used in this patient population, there is no accepted standard of care in the management of HER2+ metastatic breast cancer once the disease has progressed after multiple lines of treatment.1-3 Without clear consensus guidelines, and with no data to support the superiority of one regimen over another, treating these patients can be particularly challenging.2-5

Difficult choices Therapies that target HER2-overexpressing tumor cells have revolutionized treatment for women with HER2+ disease. However, once these patients progress after several lines of therapy, existing treatment options offer limited efficacy and may not be tolerated well by patients.2,4,6 Some patients may stop responding to treatment altogether, or may refuse active treatment, valuing quality of life over the limited results they are likely to achieve.4,7

New answers are required Patients with heavily pretreated HER2+ metastatic breast cancer need treatment options that can give you clearer answers the next time you ask yourself, “What’s next?” A pioneer in HER-signaling research, Genentech remains committed to the discovery and development of medicines that help improve the lives of women with HER2+ breast cancer throughout all stages of disease. References: 1. Cardoso F, Castiglione M. Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20(suppl 4):iv15-iv18. 2. Wardley A. The need for advanced breast cancer treatment guidelines: results of an internet-based survey. Breast. 2008;17:275-281. 3. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™: Breast Cancer. V.1.2009. http://www.nccn.org. Accessed October 20, 2009. 4. Cardoso F, Di Leo A, Lohrisch C, Bernard C, Ferreira F, Piccart MJ. Second and subsequent lines of chemotherapy for metastatic breast cancer: what did we learn in the last two decades? Ann Oncol. 2002;13:197-207. 5. Kalaja VV, for the ESMO Guidelines Working Group. Recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2007;18(suppl 2):ii9-ii11. 6. Bocci G, Tuccori M, Emmenegger U, et al. Cyclophosphamidemethotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol. 2005;16:1243-1252. 7. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. Overview of resistance to systemic therapy in patients with breast cancer. In: Yu D, Hung M-C, eds. Breast Cancer Chemosensitivity. New York, NY: Springer-Verlag. 2007:1-22. Advances in Experimental Medicine and Biology; vol 608.